RESUMEN
PURPOSE: Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC). METHODS: Patients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro. RESULTS: Adenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups. CONCLUSION: Folic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Ácido Fólico/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Vitamina B 12/administración & dosificación , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Suplementos Dietéticos , Sinergismo Farmacológico , Neoplasias Esofágicas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/metabolismo , GemcitabinaRESUMEN
5-Fluorouracil (5FU) is still a major drug in combinations regimens for the treatment of colorectal cancer (CRC) both in the adjuvant and palliative setting. 5FU or its oral prodrug capecitabine is usually combined with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab. Although this improved the outcome, the overall prognosis in patients with metastasized disease is still relatively poor. Although the target for 5FU, thymidylate synthase was shown to have a predictive value, this could only predict response in a subset of patients. Given the heterogeneous and complex nature of CRC, it is likely that other aberrations can affect therapeutic response. As an alternative, we investigated Copy number alterations using oligonucleotide-based high-throughput array-comparative-genomic-hybridization (aCGH) to obtain an unbiased screening of the whole genetic spectrum. Chromosomal aberrations have been identified in 85% of CRC patients and include genomic regions harboring copy number alterations in the DNA. These alterations may change the expression of many genes and might explain the differential response to therapy as shown in recent studies with several 5FU combinations. In order to clarify new predictive parameters for 5FU, we used aCGH in a historical cohort of patients, which received treatment with single agent 5FU, and an unsupervised clustering analysis showed a statistical (p < 0.05) difference between responding and nonresponding patients. We also find that several regions showed differences between responders/non-responders, such as losses in 12p12.3-12q15 and in 18p (where TS is located) in responding patients. Genome-wide analysis may provide an additional tool to discriminate between responders and nonresponders.
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Antimetabolitos Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/farmacología , Timidilato Sintasa/genética , Adulto , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Cromosomas Humanos Par 12/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Hibridación Genómica Comparativa , Femenino , Fluorouracilo/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Resultado del TratamientoAsunto(s)
Prótesis Vascular/efectos adversos , Cuidados Paliativos/métodos , Neoplasias Pancreáticas/complicaciones , Hueso Púbico/patología , Seroma/diagnóstico , Anciano , Comorbilidad , Diabetes Mellitus Tipo 2 , Femenino , Arteria Femoral/cirugía , Humanos , Hipertensión , Dolor Musculoesquelético , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Complicaciones Posoperatorias/etiología , Seroma/complicaciones , Seroma/etiología , Procedimientos Quirúrgicos Vasculares , Neoplasias PancreáticasRESUMEN
PURPOSE: This study was performed to assess the toxicities, the maximum-tolerated dose (MTD), the pharmacokinetics and the anti-tumour activity of gemcitabine given by 24-h hepatic arterial infusion (HAI). PATIENTS AND METHODS: Patients with liver malignancies received gemcitabine by 24-h HAI, weekly x 3, every 4 weeks. On day 1 or day 8 of the first cycle, patients received one administration by 24-h intravenous infusion for pharmacokinetic comparison and to determine hepatic extraction. RESULTS: Thirteen patients received gemcitabine at the dose levels of 75, 135 and 180 mg/m(2). The MTD was 180 mg/m(2) with thrombocytopaenia as the dose-limiting toxicity. Pharmacokinetic analysis showed a significantly lower maximum gemcitabine plasma concentration (C(max): HAI, 26, 80 and 128 nM, respectively; IV, 229, 264 and 293 nM, respectively) and area under the plasma-concentration-versus-time curve (AUC(0-24h): HAI, 386, 1247 and 2033 nmol x h/L, respectively; IV, 3526, 4818 and 5363 nmol x h/L, respectively) during HAI, compared with intravenous infusion (both P<0.001). Additionally, the mean hepatic extraction ratios of gemcitabine at the 75, 135 and 180 mg/m(2) dose level were 0.89, 0.75 and 0.55, respectively. Hepatic extraction decreased linearly with increasing dose. The C(max) and AUC(0-24h) of 2',2'-difluoro-2'-deoxyuridine, the deaminated product of gemcitabine, were similar for HAI and intravenous infusion. Seven patients had stable disease for a median duration of 9 months (range: 2-11 months). CONCLUSIONS: Gemcitabine given by 24-h HAI was well tolerated and resulted in significantly lower systemic gemcitabine plasma concentrations than intravenous infusion due to a relatively high hepatic extraction.
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Antimetabolitos Antineoplásicos , Desoxicitidina/análogos & derivados , Neoplasias Hepáticas , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Femenino , Arteria Hepática , Humanos , Infusiones Intraarteriales , Infusiones Intravenosas , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Trombocitopenia/etiología , Resultado del Tratamiento , GemcitabinaRESUMEN
Glioblastoma multiforme (GBM), the most frequent malignant brain tumor, has a poor prognosis, but is relatively sensitive to radiation. Both gemcitabine and its metabolite difluorodeoxyuridine (dFdU) are potent radiosensitizers. The aim of this phase 0 study was to investigate whether gemcitabine passes the blood-tumor barrier, and is phosphorylated in the tumor by deoxycytidine kinase (dCK) to gemcitabine nucleotides in order to enable radiosensitization, and whether it is deaminated by deoxycytidine deaminase (dCDA) to dFdU. Gemcitabine was administered at 500 or 1000 mg/m(2) just before surgery to 10 GBM patients, who were biopsied after 1-4 h. Plasma gemcitabine and dFdU levels varied between 0.9 and 9.2 microM and 24.9 and 72.6 microM, respectively. Tumor gemcitabine and dFdU levels varied from 60 to 3580 pmol/g tissue and from 29 to 72 nmol/g tissue, respectively. The gene expression of dCK (beta-actin ratio) varied between 0.44 and 2.56. The dCK and dCDA activities varied from 1.06 to 2.32 nmol/h/mg protein and from 1.51 to 5.50 nmol/h/mg protein, respectively. These enzyme levels were sufficient to enable gemcitabine phosphorylation, leading to 130-3083 pmol gemcitabine nucleotides/g tissue. These data demonstrate for the first time that gemcitabine passes the blood-tumor barrier in GBM patients. In tumor samples, both gemcitabine and dFdU concentrations are high enough to enable radiosensitization, which warrants clinical studies using gemcitabine in combination with radiation.
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Neoplasias Encefálicas/metabolismo , Desoxicitidina/análogos & derivados , Glioblastoma/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Adulto , Anciano , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/uso terapéutico , Disponibilidad Biológica , Biopsia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Citidina Desaminasa , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapéutico , Desoxicitidina Quinasa/metabolismo , Femenino , Floxuridina/sangre , Floxuridina/farmacocinética , Floxuridina/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Nucleósido Desaminasas/metabolismo , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , GemcitabinaRESUMEN
A 47-year-old man, who presented with dyspnoea, gynaecomasty, and aphasia due to an extensively metastasized malignancy, was transferred to the hospital for chemotherapy as a matter of urgency. Because of his severe clinical symptoms, the widespread presence of metastases on radiological examination, and a striking increase in serum human chorionic gonadotrophin (HCG), the patient was treated with bleomycin, etoposide, and cisplatin (BEP) for a suspected metastasized germ-cell tumour. Definitive histology, however, revealed not a germ-cell tumour, but instead a large-cell undifferentiated HCG-producing carcinoma of uncertain primary origin. Using this patient's history, ectopic HCG production by malignancies is described in more detail.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Grandes/metabolismo , Gonadotropina Coriónica/sangre , Metástasis de la Neoplasia/diagnóstico , Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Células Grandes/patología , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patologíaRESUMEN
OBJECTIVE: This study evaluated a psychosocial screening intervention that offers cancer patients counselling. The assumption underlying the intervention was that barriers are often present that hamper patients' awareness of and active request for psychosocial care. An active yet unobtrusive approach was hypothesized to improve accessibility to psychosocial services. METHODS: In a sequential cohort design, patients newly admitted to the oncology department of an academic hospital were assigned to a usual care group (n=50) or a screening group (n=79). A retrospective, medical records group (n=89) was also included. At baseline and 4 weeks following discharge, the usual care and screening groups completed mental health and quality of life questionnaires. RESULTS: Half the screening group actually wanted and received counselling. At follow-up, the screening group reported significantly less pain, better mental health and better physical and role functioning than the usual care group. CONCLUSION: The face-to-face screening intervention appears an effective means of identifying patients interested in obtaining formal psychosocial counselling, and may result in improvements in physical and mental health outcomes. PRACTICE IMPLICATIONS: This screening intervention may be particularly useful for hospitals that prefer a personal approach to psychosocial screening, but do not have sufficient resources to interview every new patient.
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Neoplasias/enfermería , Aceptación de la Atención de Salud , Calidad de Vida , Derivación y Consulta , Estrés Psicológico/prevención & control , Estudios de Cohortes , Consejo , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias/psicología , Países Bajos , Análisis de RegresiónRESUMEN
The purpose of this study was to investigate the cardioprotective effect of the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) on doxorubicin (DOX)-induced cardiotoxicity in a phase II study in patients with metastatic cancer. Eight patients with metastatic cancer were treated with DOX preceded by a 10 min i.v. infusion of 1500 mg m(-2) monoHER. Five patients were examined by endomyocardial biopsy after reaching a cumulative dose of 300 mg m(-2). Histopathological changes in the cardiomyocytes (Billingham score) were compared with those described in literature for patients treated with DOX only. The mean biopsy score of the patients was higher (2.7) than the mean score (1.4) of historical data of patients who received similar cumulative doses of DOX. Although there is a considerable variability in few investigated patients, it was indicative that monoHER enhanced DOX-induced cardiotoxicity. However, the antitumour activity of DOX seemed better than expected: three of the four patients with metastatic soft-tissue sarcoma had a partial remission and the fourth patient stable disease. It is likely that the relatively high dose of monoHER is responsible for the lack of cardioprotection and for the high response rate in patients with soft-tissue sarcoma possibly by depleting the glutathione defense system in both heart and tumour.
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Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , Cardiopatías/prevención & control , Hidroxietilrutósido/análogos & derivados , Neoplasias/tratamiento farmacológico , Adulto , Femenino , Cardiopatías/inducido químicamente , Humanos , Hidroxietilrutósido/uso terapéutico , Masculino , Persona de Mediana Edad , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patologíaRESUMEN
BACKGROUND: Ewing's sarcoma and peripheral primitive neuroectodermal tumours (PNET) are rare tumours and closely related. They occur most often in children and adolescents. Few studies have been published on treatment outcome in adult patients. METHODS: We performed a retrospective analysis of patients aged >16 years who were primarily treated at our university hospital for Ewing's sarcoma or PNET. In general, treatment consisted of long-term multiagent chemotherapy, interrupted by individualised local treatment consisting of surgery and/or radiotherapy. We reviewed clinical features and outcomes to present our experience with Ewing's sarcoma and PNET in adults. RESULTS: From 1979 to 2002, 27 patients with Ewing's sarcoma (20) or PNET (7) were treated. There were 22 men and 5 women, with a median age of 25 years (range 17-49). Ten patients presented with metastases predominantly in lungs (4) or bones (6). Combination therapy consisted of chemotherapy (27), surgery (16) and radiotherapy (16). After a median follow-up of ten years, 14 patients have died (toxicity = 2, progressive disease = 12) and 13 patients are alive and free of disease. Five-year overall survival was 58%. All four patients with bone metastases died, while all five patients presenting with lung metastases are disease-free. CONCLUSION: The five-year overall survival of 58% in this small series on adult patients is in line with paediatric study outcomes. Patients with lung metastases may even be cured by multimodality therapy. We therefore strongly advocate referral of patients with this rare disease to a specialised oncology centre.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Óseas/tratamiento farmacológico , Tumores Neuroectodérmicos Periféricos Primitivos/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Neoplasias Óseas/patología , Neoplasias Óseas/radioterapia , Neoplasias Óseas/cirugía , Terapia Combinada , Ciclofosfamida/administración & dosificación , Dactinomicina/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Ifosfamida/administración & dosificación , Estimación de Kaplan-Meier , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Países Bajos , Tumores Neuroectodérmicos Periféricos Primitivos/radioterapia , Tumores Neuroectodérmicos Periféricos Primitivos/cirugía , Estudios Retrospectivos , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/cirugía , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
A fast, sensitive and accurate method for the determination of gemcitabine (difluorodeoxycytidine; dFdC) and deoxycytidine (CdR) in human plasma/tissue was developed using LC-MS/MS techniques. Effectiveness of the method is illustrated with the analysis of plasma from a phase I trial of dFdC administered as a 24h infusion. The method was developed using (15)N(3) CdR as an internal standard across the concentration range of 1-500ng/ml, using a cold alcohol-protein precipitation followed by desorption with freeze drying. Sample clean-up for LC-MS/MS analysis was performed by an innovative liquid/liquid back extraction with ethyl acetate and water. Chromatography was performed using a Chrompak-spherisorb-phenyl-column (3.1mmx200mm, 5microm) with a 50mM formic acid: acetonitrile (9:1) mobile phase eluted at 1ml/min. Extracted samples were observed to be stable for a minimum of 48h after extraction when kept at 4 degrees C. Detection was performed using an atmospheric pressure chemical ionization (APCI) source and mass spectrometric positive multi-reaction-monitoring-mode (+MRM) for dFdC (264 m/z; 112 m/z), CdR (228 m/z; 112 m/z), and (15)N(3) CdR (231 m/z; 115 m/z) at an ion voltage of +3500V. The accuracy, precision and limit-of-quantitation (LOQ) were as follows: dFdC: 99.8%, +/-7.9%, 19nM; CdR: 100.0%, +/-5.3%, 22nM, linear range LOQ to 2microM. During 24h infusion dFdC levels were detected with no interference from either CdR or difluorodeoxyuridine (dFdU). CdR co-eluted with dFdC but selectivity demonstrated no "crosstalk" between the compounds. In conclusion the analytical assay was very sensitive, reliable and robust for the determination of plasma and tissue concentrations of dFdC and CdR.
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Desoxicitidina/análogos & derivados , Desoxicitidina/análisis , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión , Ensayos Clínicos Fase I como Asunto , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Humanos , Reproducibilidad de los Resultados , Distribución Tisular , GemcitabinaRESUMEN
Deoxycytidine (CdR) analogs are increasingly popular as chemotherapeutic agents and their effectiveness can be linked to the direct competition with active forms of endogenous CdR. A tandem mass spectrometric assay was developed to determine the plasma concentrations of CdR. Plasma extracts were prepared by protein precipitation and an ethyl acetate/water back extraction, and then separated chromatographically. Detection parameters were optimized for multi-reaction monitoring (MRM) tandem mass spectrometry and assay efficiency was improved using 15N3 CdR as an isotopic internal standard. Preliminary results from a gemcitabine trial are shown which indicate that CdR concentrations increase systemically during infusion, from about 5 nM to 78 nM after hepatic artery infusion and to 102 nM after systemic infusion for 24 hours. The developed assay demonstrated good sensitivity and selectivity for CdR.
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Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Desoxicitidina/biosíntesis , Desoxicitidina/farmacocinética , Antineoplásicos/farmacología , Química Clínica/métodos , Cromatografía/métodos , Desoxicitidina/sangre , Desoxicitidina/farmacología , Humanos , Espectrometría de Masas , Modelos Biológicos , Modelos Químicos , Sensibilidad y Especificidad , Factores de Tiempo , GemcitabinaRESUMEN
Absorption of a physiological dose of ferrous iron was studied in 18 patients with solid malignancy receiving epoetin therapy for mild chemotherapy-associated anemia. The historical control group consisted of 25 iron replete volunteers (iron absorption 20 +/- 11% in males and 26 +/- 13% in females) and 21 patients with uncomplicated iron deficiency (iron absorption 71 +/- 19%). Iron absorption was increased in the majority of the cancer patients (iron absorption 59 +/- 35%). There were no significant differences in iron absorption between cancer patients who were iron replete or iron deficient according to current clinical practice guidelines (iron deficiency: transferrin saturation < 20% and/or serum ferritin < 100 ng/mL). Red cell iron incorporation was not disturbed in the majority (89%) of patients.
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Anemia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , Absorción Intestinal , Hierro/metabolismo , Neoplasias/metabolismo , Adulto , Anciano , Anemia/inducido químicamente , Anemia/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Epoetina alfa , Femenino , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/administración & dosificación , Proteínas RecombinantesRESUMEN
PURPOSE: To compare the pharmacology of the paclitaxel-cisplatin, gemcitabine-cisplatin and paclitaxel-gemcitabine combinations in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-four chemo-naive patients with advanced NSCLC were randomized to receive one of the three regimens. Plasma pharmacokinetics and pharmacologic parameters in mononuclear cells were compared and related to toxicity and efficacy. RESULTS: Pharmacological parameters of gemcitabine and cisplatin were not influenced by the combination with one of the other agents, while the paclitaxel clearance was significantly lower for the combination with cisplatin as compared to gemcitabine (P=0.024). The percentage decrease in platelets was significantly higher for the gemcitabine combinations (P=0.004) and related to the dFdCTP-Cmax (P=0.030). Pharmacologic parameters were not related to response or survival. CONCLUSIONS: Gemcitabine and cisplatin pharmacology were not influenced by the combination with one of the other agents, while paclitaxel has a lower clearance in combination with cisplatin as compared to gemcitabine.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Interacciones Farmacológicas , Femenino , Semivida , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , GemcitabinaRESUMEN
BACKGROUND: Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are essential enzymes for 5-fluorouracil (5-FU) metabolism. In patients with advanced colorectal cancer (ACRC), retrospective studies have shown that low expression levels of TS and DPD correlated with response to 5-FU. We performed a prospective study in which the choice of first-line chemotherapy with either 5-FU or a non-5-FU containing regimen was based on TS and DPD expression. PATIENTS AND METHODS: Fresh-frozen samples of metastases were obtained from 58 previously untreated patients with ACRC. mRNA expression of TS and DPD was quantified using an RT-PCR assay. Patients with low tumor expression of both TS and DPD received weekly bolus 5-FU/leucovorin (LV) 500 mg/m2 (group A); patients with high TS and/or DPD received 3-weekly oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 (group B). After progression, cross-over to the alternative regimen was attempted. RESULTS: Of 53 eligible patients, 31 had tumors with both low TS and low DPD, and were treated in group A. A response was observed in 11 patients [35%; 95% confidence interval (CI) 19% to 54%]. Cross-over to second-line oxaliplatin/irinotecan resulted in a partial response in two out of 16 patients (13%; 95% CI 1% to 38%). In group B, four out of 22 patients responded (18%; 95% CI 5% to 40%), while no responses were observed in 12 patients after cross-over to 5-FU/LV (0%; 95% CI 0% to 28%). CONCLUSIONS: Prospective selection of 5-FU/LV chemotherapy based on low TS and DPD expression in patients with ACRC did not confirm the high response rates reported in retrospective studies. The procedure of obtaining metastatic tissue and quantitation of enzymes appeared feasible but cumbersome. Before assessing the clinical utility of a predictive marker in a randomized trial, future studies should focus on prospective validation of the assay in a large and well defined population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Timidilato Sintasa/metabolismo , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Dihidrouracilo Deshidrogenasa (NADP)/genética , Femenino , Fluorouracilo/administración & dosificación , Humanos , Irinotecán , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Pronóstico , Estudios Prospectivos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Timidilato Sintasa/genéticaRESUMEN
EORTC protocol 30924 is an international randomized trial reporting a 7.3 year update of a 2 weekly regimen of high-dose intensity chemotherapy with M-VAC plus granulocyte colony stimulating factor (HD-M-VAC) compared to classic M-VAC in advanced transitional cell carcinoma (TCC). Two hundred and sixty three untreated patients with bidimensionally measurable TCC were included. In an intention to treat analysis, there were 28 complete responses (CR) (21%) and 55 partial responses (PR) (41%), for an overall response rate (RR) of 64% on the HD-M-VAC arm. On M-VAC, there were 12 CR (9%) and 53 PR (41%), for an overall RR of 50% . The P-value for the difference in CR was 0.009; and for RR, was 0.06. After a median follow-up of 7.3 years, 24.6% are alive on the HD-M-VAC arm vs. 13.2% on the M-VAC arm. Median progression-free survival was better with HD-MVAC (9.5 months) vs. M-VAC (8.1 months). The mortality hazard ratio (HR) was 0.76. The 2-year survival rate for HD-M-VAC was 36.7% vs. 26.2% for M-VAC. At 5 years, the survival rate was 21.8% in the HD-M-VAC vs. 13.5%. Median survival was 15.1 months on HD-MVAC and 14.9 months on M-VAC. There was one death from toxicity in each arm; and more patients died to malignant disease in the M-VAC arm (76%) than in the HD-M-VAC arm (64.9%). With longer follow-up initial results have been confirmed, and shows that HD-M-VAC produces a borderline statistically significant relative reduction in the risk of progression and death compared to M-VAC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Análisis de Supervivencia , Vinblastina/administración & dosificaciónRESUMEN
Some anticancer agents tend to accumulate during repeated administration. We determined whether gemcitabine or its metabolites would accumulate during repeated administration. Gemcitabine was administered over two courses with each course consisting of a 30-min infusion at 1000 mg/m(2) weekly for 3 weeks followed by 1 week of rest. In 14 patients we evaluated eventual accumulation by comparing the concentrations in blood samples taken before, and at 30 and 60 min after the start of infusion on days 1, 8 and 15, in both cycles. At the end of the infusion gemcitabine concentrations at day 1 of both courses varied between 18 and 77 microM and at day 15 between 13 and 90 microM. The mean ratios day 8/day 1 and day 15/day 1 varied from 0.94 to 1.18. For the inactive metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) these values varied between 54 and 152 microM and 55 and 157, respectively, and the ratios from 0.96 to 1.08. The concentration of the active metabolite of gemcitabine, gemcitabine triphosphate (dFdCTP) in peripheral white blood cells, ranged between 37 and 283 pmol/10(6) cells at the end of infusion on day 1 and 35 and 115 pmol/10(6) cells on day 15. Potential accumulation was evaluated using a mixed effects model and no evidence was observed of accumulation for either gemcitabine or its metabolites. Gemcitabine can be administered safely without the risk that the drug will accumulate.
Asunto(s)
Antimetabolitos Antineoplásicos/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/metabolismo , Anciano , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/farmacocinética , Área Bajo la Curva , Desoxicitidina/sangre , Desoxicitidina/metabolismo , Desoxicitidina/farmacocinética , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/tratamiento farmacológico , GemcitabinaRESUMEN
The pharmacokinetics of 5-fluorouracil (5FU) have been related to toxicity and antitumor activity, in particular for continuous infusion schedules, but to a lesser extent for frequently used bolus injections. The use of intensive sampling schedules limits the application of pharmacokinetics to optimize individual dosing or to define the ideal combination with other drugs. We therefore reanalyzed a pharmacokinetic study in order to develop a limited sampling schedule. Patients received escalating doses of 5FU at 500, 600 and 720 mg/m2 as a bolus until toxicity developed. Blood samples were analyzed until 24 h after administration. The area under the concentration time curve from 0-90 min (AUC(0-90)) was strongly correlated with dose and also with toxicity (p = 0.0009). The 5FU concentrations at 30 and 60 min were correlated to the AUC(30-240) and to that of the AUC(0-90) (r2 = 0.970). The use of limited sampling (30, 60, 90 min) in a patient given 353 mg/m2 5FU with severe toxicity at initial dosing at 500 mg/m2 revealed that the AUC(0-90) at 353 mg/m2 was higher than the normal AUC(0-90) for 500 mg/m2. This patient appeared to have an 8-fold lower activity of the 5FU degradation enzyme dihydropyrimidine dehydrogenase. Limited sampling will allow us to define potential aberrant kinetics of pharmacokinetic interaction of 5FU with other drugs being developed for treatment of colorectal cancer.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Área Bajo la Curva , Neoplasias Colorrectales/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
This work was conducted to evaluate the effect of early intervention with epoetin alfa (EPO) on transfusion requirements, hemoglobin level (Hb), quality of life (QOL) and to explore a possible relationship between the use of EPO and survival, in patients with solid tumors receiving platinum-based chemotherapy. Three hundred and sixteen patients with Hb12.1g/dL were randomised 2:1 to EPO 10000 IU thrice weekly subcutaneously (n = 211) or best supportive care (BSC) (n = 105). The primary end point was proportion of patients transfused while secondary end points were changes in Hb and QOL. The protocol was amended before the first patient was recruited to also prospectively collect survival data. EPO therapy significantly decreased transfusion requirements (P < 0.001) and increased Hb (P < 0.005). EPO-treated patients had significantly improved QOL compared with BSC patients (P < 0.05). Kaplan-Meier estimates showed no differences in 12-month survival (P = 0.39), despite a significantly greater number of patients with metastatic disease in the EPO group (78% vs. 61%, P = 0.001). EPO was well tolerated. This study has shown that early intervention with EPO can result in a significant reduction of transfusion requirements and increases in Hb and QOL in patients with mild anemia during platinum-based chemotherapy.
Asunto(s)
Anemia/prevención & control , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Transfusión Sanguínea/estadística & datos numéricos , Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , Hemoglobinas/análisis , Neoplasias/tratamiento farmacológico , Platino (Metal)/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anemia/sangre , Anemia/inducido químicamente , Epoetina alfa , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Calidad de Vida , Proteínas Recombinantes , Análisis de SupervivenciaRESUMEN
BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate; Tavocept) is a novel agent developed to protect against cisplatin (cis-diammine-dichloroplatinum(II))-associated chronic toxicities. In this study, we determined the recommended dose of BNP7787 when preceding a fixed dose of cisplatin, the pharmacokinetics (PKs) and the possible reduction of saline hydration. Patients with advanced solid tumours received BNP7787 in escalating doses of 4.1-41 g m(-2) as a 15-min intravenous (i.v.) infusion followed by cisplatin 75 mg m(-2) as a 60-min i.v. infusion together with pre- and postcisplatin saline hydration in a volume of 2200 ml; cycles were repeated every 3 weeks. PK was carried out using BNP7787, cisplatin and the combination. Twenty-five patients were enrolled in stage I of the study to determine the recommended dose of BNP7787. No dose-limiting toxicity was reached. The highest dose level of 41 g m(-2) resulted in a low incidence of grade 2 toxicities, being nausea and vomiting, dry mouth or bad taste and i.v. injection site discomfort. Doses of BNP7787 > or = 18.4 g m(-2) did not show a drug interaction between BNP7787 and cisplatin. In stage II of the study, patients received a fixed dose of BNP7787 of 18.4 g m(-2) preceding cisplatin and were entered in prespecified reduced saline hydration steps. A total of 21 patients in cohorts of six to nine patients received reduced saline hydration of 1600 ml (step A), 1000 ml (step B) and 500 ml (step C). In step C, two out of six evaluable patients experienced grade 1 nephrotoxicity. Cisplatin acute toxicities in all 46 patients were as expected. Only five patients complained of paresthesias grade 1 and six developed slight audiometric changes. Partial tumour response was observed in four patients and stable disease in 15 patients. In conclusion, BNP7787 was tolerated well up to doses of 41 g m(-2). The recommended dose of 18.4 g m(-2) enabled safe reduction of the saline hydration schedule for cisplatin to 1000 ml. Further studies will assess whether BNP7787 offers protection against platinum-related late side effects.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Deshidratación/prevención & control , Mesna/análogos & derivados , Mesna/administración & dosificación , Mesna/farmacocinética , Neoplasias/tratamiento farmacológico , Adulto , Cisplatino/efectos adversos , Femenino , Humanos , Enfermedades Renales/prevención & control , Masculino , Mesna/efectos adversos , Persona de Mediana Edad , Neoplasias/metabolismoRESUMEN
In a panel of 18 colon cancer cell lines we found that the thymidylate synthase (TS) genotype was related to TS enzyme activity, but not to TS protein and mRNA levels. In addition, no relation with drug sensitivity was observed. TS genotyping of different tissues from 78 colorectal cancer patients revealed a high level of homology in polymorphic status between normal and malignant tissues and the heterozygous genotype to be the most frequent.