RESUMO
BACKGROUND: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS: 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION: We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.
Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Indóis/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Benzamidas , Método Duplo-Cego , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Sunitinibe , Análise de Sobrevida , Resultado do TratamentoRESUMO
Recent publications have suggested that imatinib (Glivec) may be cardiotoxic. We have therefore assessed the largest study on the agent performed in patients with gastrointestinal stromal tumours, randomising a daily dose of 400mg versus 800 mg. 946 Patients were entered, 942 patients received at least one dose of imatinib. The median time on treatment was 24 months. A total of 24,574 exposure months could be analysed. We could not identify an excess of cardiac events in the study population. In 2 patients (0.2%) a possible cardiotoxic effect of imatinib could not fully be excluded. The current analysis of a large randomised prospective study could not confirm previous suggestions of imatinib induced cardiac toxicity.
Assuntos
Antineoplásicos/efeitos adversos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Insuficiência Cardíaca/induzido quimicamente , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
PURPOSE: The aim of this study was to identify factors predicting initial and late resistance of GI stromal tumor (GIST) patients to imatinib and to document the dose-response relationship in the prognostic subgroups. This study is based on the European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group randomized trial comparing two doses of imatinib in advanced disease. PATIENTS AND METHODS: Initial resistance was defined as progression within 3 months of randomization, and late resistance was defined as progression beyond 3 months. Investigated cofactors include imatinib dose, age, sex, performance status, original disease site, site and size of lesions at trial entry, and baseline hematologic and biologic parameters. RESULTS: Initial resistance was recorded for 116 (12%) of 934 assessable patients and was independently predicted by the presence of lung and absence of liver metastases, low hemoglobin level, and high granulocyte count. Among 818 patients who were alive and progression free at 3 months, 347 subsequent progressions were recorded, and late resistance was independently predicted by high baseline granulocyte count, primary tumor outside of the stomach, large tumor size, and low initial imatinib dose. The impact of initial dose on late resistance was mainly significant in patients with a high baseline granulocyte count (> 5.10(9)/L) and in patients with tumors of GI origin outside of the stomach and small intestine. CONCLUSION: Our study identifies patients for whom initial and/or long-term treatment needs to be improved and patients who require a high initial dose. Correlation of these results with immunohistochemistry and molecular parameters may further help to understand the biologic mechanisms of resistance.
Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Benzamidas , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
PURPOSE: A randomized phase II/III trial was conducted to determine whether combination treatment with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN-alpha-2a) was superior to IFN-alpha-2a alone in patients with progressive metastatic renal cell carcinoma. PATIENTS AND METHODS: Three hundred twenty patients were randomly assigned to treatment with IFN-alpha-2a plus 13-CRA or to IFN-alpha-2a alone. IFN-alpha-2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU by increments of 3 MU. Patients randomly assigned to combination therapy received oral 13-CRA 1 mg/kg/d plus IFN-alpha-2a. RESULTS: Median time to progression was 5.1 months for patients treated with the combination and 3.4 months for patients on IFN-alpha-2a alone (P = .008). Progression-free survival rates at 6 months were 43% for patients receiving combined therapy and 30% for patients on IFN-alpha-2a, and at 12 months, 27% and 17%, respectively. Median overall survival was 17.3 months for patients on IFN-alpha-2a and 13-CRA, and 13.2 months for patients treated with IFN-alpha-2a (P = .048). Twenty-two percent of the patients receiving the combination stopped treatment due to toxicity, as compared with 16% on IFN-alpha-2a. CONCLUSION: Progression-free and overall survival for patients with progressive metastatic renal cell carcinoma treated with IFN-alpha-2a plus 13-CRA were significantly longer compared with patients on IFN-alpha-2a alone (P = .007 and P = .048, respectively). Improvement in efficacy in the combination arm was accompanied by increased, though not serious, toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Interferon-alfa/administração & dosagem , Isotretinoína/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Administração Oral , Adulto , Idoso , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Interferon alfa-2 , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate-binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib. METHODS: Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Steady-state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d. Genotyping was carried out via direct sequencing or restriction fragment length polymorphism-based techniques. RESULTS: Human embryonic kidney 293 cells transfected with ABCG2 Q141K exhibited greater drug accumulation in vitro in comparison with cells expressing wild-type ABCG2 (P = .028). However, pharmacokinetic parameters of imatinib in vivo were not statistically significantly different in 16 patients who were heterozygous for ABCG2 421C>A compared with 66 patients carrying the wild-type sequence (P = .479). The apparent oral clearance of imatinib was potentially reduced in individuals with at least 1 CYP2D6*4 allele (median, 7.78 versus 10.6 L/h; P = .0695). Pharmacokinetic parameters were not related to any of the other multiple-variant genotypes (P >or= .230), possibly because of the low allele frequencies. CONCLUSIONS: This study indicates that common genetic variants in the evaluated genes have only a limited impact on the pharmacokinetics of imatinib. Further investigation is required to quantitatively assess the clinical significance of homozygous variant ABCG2 and CYP2D6 genotypes in patients treated with imatinib.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Preparações Farmacêuticas/metabolismo , Piperazinas/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacocinética , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Benzamidas , Transporte Biológico Ativo , Linhagem Celular Tumoral , Estudos de Coortes , Sistema Enzimático do Citocromo P-450/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Frequência do Gene , Genótipo , Humanos , Mesilato de Imatinib , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteínas Proto-Oncogênicas c-kit/genética , Células Estromais/metabolismoRESUMO
The aim of this study was to identify prognostic factors for toxicity to treatment with imatinib. The study was based on 942 patients with gastrointestinal stromal tumours (GIST) randomised to receive imatinib at different doses. The correlation between toxicities occurring with a Common Toxicity Criteria (CTC) grade 2 or more (non-haematological) or grade 3 or 4 (haematological) and imatinib dose, age, sex, performance status, original disease site, site and size of lesions at trial entry, baseline haematological and biological parameters was investigated. Anaemia was correlated with dose and baseline haemoglobin level, and neutropaenia with baseline neutrophil count and haemoglobin level. The risk of non-haematological toxicities was dose dependent and higher in females (oedema, nausea, diarrhoea), and in patients of advanced age (oedema, rash fatigue), poor performance status (fatigue and nausea), prior chemotherapy (fatigue), tumour of identified gastrointestinal origin (diarrhoea) and small lesions (rash). A multivariate risk calculator that can be used in the clinic for individual patients is proposed.
Assuntos
Antineoplásicos/efeitos adversos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Adulto , Idoso , Benzamidas , Protocolos Clínicos , Feminino , Humanos , Mesilato de Imatinib , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P<0.0001) and the relative risk of death by 190% (P<0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P<0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.
Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação/genética , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/uso terapêutico , Adulto , Idoso , Benzamidas , Intervalo Livre de Doença , Éxons , Feminino , Tumores do Estroma Gastrointestinal/genética , Genótipo , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
PURPOSE: To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules. EXPERIMENTAL DESIGN: Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks. Patients were randomly assigned to take the drug along with a high-fat, high-calorie breakfast for the administration at day 1 of the first or second cycle. Dosages tested were 70 and 80 mg/m(2)/day. RESULTS: Twenty-five patients received 101 cycles of therapy (median two cycles, range 1-15). During the first cycle, grade 3 delayed diarrhea and grade 3 fever were the DLTs at the dosage of 80 mg/m(2)/day in three out of five patients. Hematologic and nonhematologic toxicities were mild to moderate. Exposure to the active metabolite SN-38 was relatively high compared with i.v. infusion, but no relevant accumulation was observed. Food had no significant effect on irinotecan pharmacokinetics. One confirmed partial remission and 10 disease stabilizations were observed in previously treated patients. No association was found between the UGT1A1*28 genotype and the risk of severe irinotecan-induced toxicity. CONCLUSIONS: For oral irinotecan, a dose of 70 mg/m(2)/day for 5 consecutive days every 3 weeks is recommended for further studies. Delayed diarrhea was the main DLT, similar to that observed with intravenously administered irinotecan. This study confirms that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Anemia/induzido quimicamente , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Cápsulas , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Diarreia/induzido quimicamente , Gorduras na Dieta/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Genótipo , Glucuronosiltransferase/genética , Humanos , Irinotecano , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/genética , Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Trombocitopenia/induzido quimicamente , Fatores de Tempo , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
PURPOSE: This phase I study was conducted to assess the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor tyrosine kinase inhibitor PKI166 in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: PKI166 was first given once daily continuously and in the second part of the study once daily for 2 weeks every 4 weeks to establish the maximum tolerated dose (MTD). Ten additional patients were studied at MTD to acquire additional safety information and characterize the effect of food intake on PKI166 pharmacokinetics. Pharmacokinetics of PKI166 were characterized after single and multiple doses at all dose levels. RESULTS: Fifty-four patients received a total of one hundred sixteen 28-day cycles of PKI166. Dose-limiting transaminase elevations were observed in two of seven and two of eight patients using 50 and 100 mg PKI166 continuously. In the second part with PKI166 once daily for 2 weeks every 4 weeks, MTD was set at 750 mg. Dose-limiting toxicity consisted of diarrhea, skin rash, and transaminase elevations. Pharmacokinetic analysis revealed fast absorption, a linear dose-response relationship without drug accumulation after multiple doses. At MTD, no significant influence of food intake on PKI166 pharmacokinetics was observed. Stable disease for more than two cycles was observed in 11 patients. CONCLUSIONS: PKI166 given once daily for 2 weeks every 4 weeks is well tolerated with linear pharmacokinetics, compatible with once daily dosing, and without significant effect of food intake on absorption. The recommended dose for further studies is 750 mg once daily for 2 weeks every 4 weeks.
Assuntos
Receptores ErbB/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Pirróis/farmacocinética , Pirróis/uso terapêutico , Absorção , Adulto , Idoso , Antineoplásicos/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Modelos Químicos , Proteínas Tirosina Quinases/metabolismo , Software , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The signal transduction inhibitor imatinib is one of the latest breakthroughs in cancer pharmacotherapy. It is administered orally over prolonged periods of time for the treatment of gastro-intestinal stromal tumours. Routine therapeutic drug monitoring of blood plasma versus red blood cells over several years by liquid chromatography coupled tandem mass spectrometry has high-lighted a very intriguing phenomenon. Imatinib plasma availability decreases dramatically owing to a significant shift in the partition ratio of red blood cells versus plasma. The shift is enforced by combination with everolimus, another signal transduction inhibitor. These data warrant routine erythrocyte versus plasma monitoring to prevent unexpected alterations in drug efficacy during long-term treatment.
Assuntos
Antineoplásicos/sangue , Eritrócitos/metabolismo , Imunossupressores/farmacologia , Piperazinas/sangue , Pirimidinas/sangue , Sirolimo/análogos & derivados , Benzamidas , Resistencia a Medicamentos Antineoplásicos , Eritrócitos/efeitos dos fármacos , Everolimo , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Mesilato de Imatinib , Técnicas In Vitro , Espectrometria de Massas , Plasma/química , Plasma/metabolismo , Sirolimo/farmacologia , Neoplasias Gástricas/metabolismoRESUMO
PURPOSE: We previously found a statistically significant number of cytokeratin 19 (CK19)+ cells in peripheral blood (PB) of stage IV breast cancer (BC) patients compared with those of healthy volunteers, using a quantitative real-time reverse transcription-PCR. We aimed to apply the technique on bone marrow (BM) of primary operable BC patients. Pre- and postoperative PB samples of these patients were further analyzed to investigate possible shedding of CK19+ cells during the operation. EXPERIMENTAL DESIGN: In 54 primary operable BC patients, we analyzed 50 BM samples taken preoperatively and 297 PB samples. PB samples were collected before surgery; immediately after surgery; on the first, second, and fifth day postoperatively; and one month postoperatively. RESULTS: In BM of controls and BC patients, we detected a median of 28 and 568 CK19+ cells/5 x 10(6) leukocytes, respectively (P < 0.001). In preoperative blood (B-1) samples, we measured a median of 109 CK19+ cells. Using the upper limit of 95% confidence interval of controls as cutoff, 74% and 52% of BM and (B-1), respectively were considered CK19+. There was no significant correlation between CK19+ cells in BM and (B-1) and classical prognostic factors. We found no significant difference between blood samples at different time points with respect to the average CK19+ cells. CONCLUSIONS: In primary BC patients, we detected high numbers of CK19+ cells in BM and PB (B-1) samples compared with controls. However, no significant correlation between the presence of CK19+ cells in BM and PB and classical prognostic factors was found. We detected no statistically significant influence of surgical manipulation on CK19+ cells.
Assuntos
Neoplasias da Mama/sangue , Queratinas/genética , RNA Mensageiro/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Células da Medula Óssea/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Primers do DNA , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Período Pós-Operatório , Cuidados Pré-Operatórios , Prognóstico , RNA Neoplásico/sangue , Células Tumorais CultivadasRESUMO
Sarcomas--like leukemias, which are also mesodermal malignancies--carry biological significance disproportionate to their clinical frequency. Identification of mutations and translocations associated with these tumors has illuminated aberrant signaling pathways that cause these diseases, determine their behavior, and are therapeutic targets. Activated receptor-associated tyrosine kinase c-kit, mutated in most gastrointestinal stromal tumors, has proven a clinically effective target for enzyme inhibition. A translocation involving a single gene family, consisting of EWS and related genes, has been identified in five different sarcomas, and its chimeric protein products could prove similarly amenable to inhibitors. Resolution of the histopathological complexity is being aided by data from molecular and chromosomal characterization. Improvements in imaging, definition of prognostic factors, and surgical and radiotherapeutic treatment have resulted in improved local control. Continued progress will depend on further adapting the rapidly evolving technologies of genomics and proteomics. It will also depend upon accurate histopathological diagnosis based on validated reagents and consistent methodologies applied to adequate tissue samples derived from patients with complete clinical data. Finally, multicenter, coordinated trials, such as those that occurred with assessment of imatinib mesylate in metastatic gastrointestinal stromal tumors, will assure the most rapid reductions in morbidity and mortality.
Assuntos
Sarcoma/terapia , Adulto , Quimioterapia Adjuvante , Aberrações Cromossômicas , Humanos , Cariotipagem , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Retroperitoneais/terapia , Sarcoma/genética , Sarcoma/patologiaRESUMO
In a phase I study conducted by the EORTC Soft Tissue and Bone Sarcoma Group, 40 patients with advanced soft tissue sarcomas, most of whom had gastrointestinal stromal tumors (GISTs), received imatinib at doses of 400 mg q.d., 300 mg b.i.d., 400 mg b.i.d., or 500 mg b.i.d. Dose-limiting toxicities, including severe nausea, vomiting, edema and rash, were seen at the highest dose level; the maximum tolerated dose was therefore 400 mg b.i.d. Imatinib was active in the group of 35 patients with GISTs, producing partial responses in 19 (54%) patients and stable disease in 13 patients (37%). Responding patients have now been followed for a minimum of 10 months. The most common side effects seen in patients continuing on therapy have been periorbital edema (40%), peripheral edema (37.5%), fatigue (30%), skin rash (30%) and nausea/vomiting (25%). Severe late myelosuppression has also been seen occasionally. Eighteen (51%) GIST patients continue to have partial responses and 11 (31%) continue with stable disease. Thus, 82% of patients with GISTs are still obtaining clinically important benefits with continued imatinib therapy. Some patients showed accelerated progressive disease shortly after starting imatinib. On the other hand, following drug withdrawal, 2 patients had reductions in tumor burden and remain alive without drug therapy. In summary, imatinib is generally well tolerated and has significant activity during long-term treatment of patients with advanced GISTs.
Assuntos
Antineoplásicos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias de Tecido Conjuntivo/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Sarcoma/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Benzamidas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Mesilato de Imatinib , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Células Estromais , Resultado do TratamentoRESUMO
Modifications to bodily functions and physiology are known to occur with age. These changes can have a considerable impact on the pharmacokinetic processes of absorption, distribution, metabolism and excretion and the pharmacodynamic properties of administered drugs. For many drugs with a high therapeutic index, this will be clinically unimportant, but for anticancer drugs, which usually have a low therapeutic index, these pharmacological changes can lead to dramatic consequences, such as excessive drug concentrations and unacceptable toxicity, or subtherapeutic drug concentrations and ineffective treatment. Despite the increased susceptibility of the elderly to these changes, doses are rarely adapted on the basis of pharmacokinetics and pharmacodynamics, with the exception of changes secondary to altered renal function. Until recently, only a few large prospective randomised trials have provided evidence-based data for dose adaptations in elderly patients. However, with increasing knowledge of the pharmacokinetics of anticancer drugs, advances in the knowledge of pharmacokinetic behaviour with aging, and documented efficacy and toxicity data in the elderly population, it is possible to highlight aspects of prescribing anticancer drugs in the elderly. In general, and for most drugs, age itself is not a contraindication to full-dose chemotherapy. The main limiting factors are comorbidity and poor functional status, which may be present in a significant number of the elderly population. Elderly patients with cancer are part of the daily practice of oncologists, but currently clinicians can often only estimate whether dose modification is advantageous for the elderly. This review attempts to elucidate the factors that can influence the pharmacokinetics of anticancer drugs frequently used in the elderly, and the clinical or biochemical parameters that form the basis for dose adjustments with age.
Assuntos
Envelhecimento , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Interações Medicamentosas , Idoso Fragilizado , Humanos , Neoplasias/tratamento farmacológico , Cooperação do Paciente , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
An isocratic high-performance liquid chromatographic method coupled to tandem mass spectrometry for the quantification of the revolutionary and promising anticancer agent STI-571 (tradenames Gleevec, Glivec, Imatinib) in blood plasma and red blood cells (RBCs) is described. The method involves measurement of sediment technology for RBCs and a subsequent single protein precipitation step by the addition of acetonitrile to both the RBC isolate and plasma. The sample mixture was centrifuged (10 min, 3600 g), and the supernatant filtered through a HPLC filter (0.45 microm). The analytes of interest, STI-571 and the internal standard [2H8]STI-571 were eluted on a Waters Symmetry C18 column (50x2.1 mm I.D., 3.5 microm particle size) using a methanol-0.05% ammonium acetate (72:28, v/v) mixture. STI-571 and [2H8]STI-571 were detected by electrospray tandem mass spectrometry in the positive mode, and monitored in the multiple reaction monitoring transitions 494>394 and 502<394, respectively. The lower limit of quantitation of STI-571 was 2.1 ng/ml in RBCs and 1.8 ng/ml in plasma. The recovery from both plasma and RBCs was between 65 and 70%. The method proved to be robust, allowing simultaneous quantification of STI-571 in RBCs and plasma with sufficient precision, accuracy and sensitivity and is useful in monitoring the fate of this signal transduction inhibitor in whole blood of cancer patients.
Assuntos
Antineoplásicos/sangue , Eritrócitos/química , Piperazinas/sangue , Pirimidinas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Benzamidas , Humanos , Mesilato de Imatinib , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
We investigated the potential chemosensitizing effect of nicotinamide on CPT-11, and the relationship between nicotinamide and CPT-11, intratumoral drug uptake in syngeneic rhabdomyosarcoma tumors in rats. Pretreatment with nicotinamide, known to improve tumor oxygenation, perfusion and radiotherapy effect, only caused a minor increase in tumor growth delay. To our surprise, intratumoral uptake of CPT-11 and its active metabolite SN-38 decreased significantly between 19% and 43%. This discrepancy suggests that the potential chemosensitizing effect of nicotinamide, seen in other studies, is based on a direct effect on tumor cells rather than on an increased delivery of anticancer drugs. A second finding is that plasma levels of CPT-11 and SN-38 respectively increase and decrease after nicotinamide exposure, suggesting inhibition of carboxylesterase, which is necessary for the conversion of CPT-11 to its active metabolite SN-38. Great care is required when combining nicotinamide with anticancer drugs, since unexpected pharmacokinetic and pharmacodynamic alterations might occur.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Niacinamida/farmacologia , Pró-Fármacos/farmacologia , Rabdomiossarcoma/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/farmacocinética , Disponibilidade Biológica , Camptotecina/sangue , Camptotecina/farmacocinética , Interações Medicamentosas , Irinotecano , Pró-Fármacos/farmacocinética , Ratos , Rabdomiossarcoma/sangueRESUMO
OBJECTIVES: To evaluate the antitumor response, time-to-event efficacy endpoints and toxicity of plitidepsin (Aplidin) 5 mg/m as a 3-hour intravenous (i.v.) infusion every 2 weeks in patients with unresectable advanced medullary thyroid carcinoma (MTC). METHODS: Sixteen patients with MTC and disease progression or large tumor burden received plitidepsin. Tumor response and time-related parameters were evaluated according to Response Evaluation Criteria in Solid Tumors. Secondary efficacy endpoints were marker response (calcitonin and carcinoembryonic antigen), clinical benefit and quality of life. Safety was assessed using the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 141 cycles (median, 9 per patient; range, 1-24) were administered. No complete responses or partial responses (PR) were found, and 12 patients had stable disease for >8 weeks. Median follow-up was 15.0 months. Median time to progression was 5.3 months. Median overall survival could not be calculated, but 86.7% and 66.0% of patients were alive at 6 and 12 months. Marker response included 1 unconfirmed PR and 2 stabilizations for calcitonin, and 1 unconfirmed PR and 4 stabilizations for calcitonin and carcinoembryonic antigen. One patient showed clinical benefit. Quality of life scores generally decreased during the study. Most treatment-related adverse events were mild or moderate. Grade 3 lymphopenia was the only severe hematological toxicity found (2 patients). Severe nonhematological toxicities were grade 3 creatine phosphokinase increase (2 patients, with no myalgia or muscular weakness) and transient grade 3 alanine aminotransferase increase (5 patients). CONCLUSIONS: Single-agent plitidepsin given as 3-hour i.v. infusions every 2 weeks was generally well tolerated but showed limited clinical activity in patients with unresectable advanced MTC.
Assuntos
Neoplasias do Tronco Encefálico/tratamento farmacológico , Depsipeptídeos/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Neoplasias do Tronco Encefálico/secundário , Feminino , Humanos , Infusões Intravenosas , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Peptídeos Cíclicos , Prognóstico , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/patologia , Resultado do TratamentoRESUMO
PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB). PATIENTS AND METHODS: Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible. The SWOG study confirmed t(17;22) after enrollment. RESULTS: Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively. Tumor size ranged from 1.2 to 49 cm. DFSP was located on head/neck, trunk, and limb in seven, 11, and six patients, respectively, and was classic, pigmented, and fibrosarcomatous DFSP in 13, one, and nine patients, respectively. Metastases were present in seven patients (lung involvement was present six patients). Eleven patients (4%) had partial response as best response, and four patients had progressive disease as best response. Median time to progression (TTP) was 1.7 years. Imatinib was stopped in 11 patients because of progression, one patient because of toxicity, and two patients after complete resection of disease. Median overall survival (OS) time has not been reached; 1-year OS rate was 87.5%. CONCLUSION: Imatinib is active in DFSP harboring t(17;22) including fibrosarcomatous DFSP, with objective response rate approaching 50%. Response rates and TTP did not differ between patients taking 400 mg daily versus 400 mg twice a day.
Assuntos
Antineoplásicos/uso terapêutico , Dermatofibrossarcoma/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Benzamidas , Ensaios Clínicos Fase II como Assunto , Dermatofibrossarcoma/mortalidade , Esquema de Medicação , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversosRESUMO
BACKGROUND: In the treatment of extensive liver metastasis of breast cancer (LMBC), locally administered Mitomycin C (MMC) to the liver might be an effective approach with limited toxicity. PATIENTS AND METHODS: We retrospectively reviewed the records of 30 patients with LMBC treated with intra-hepatic MMC at our institution. MMC (12 mg) was administered by transcatheter bolus infusion into the hepatic arteries every 4 weeks. Tumour response according to RECIST criteria, progression free survival (PFS), overall survival (OS) and duration of response (DR) were used to evaluate efficacy. RESULTS: There was a local response in the liver and a global response in respectively 33 and 26%. The median PFS, DR and OS were 3, 4 and 7 months, respectively. There was more benefit in patients without documented metastases outside the liver and without severe liver dysfunction. Thrombocytopenia, leucocytopenia and an allergic reaction were observed after MMC administration in 20 (67%), 12 (40%) and 4 patients (13%), respectively. CONCLUSION: Intra-hepatic MMC bolus infusion as treatment of extensive LMBC is associated with limited toxicity and has a significant response rate in the liver. Prospective investigations are required to define the place of this modality for treating patients with breast cancer liver metastases.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias da Mama/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Mitomicina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Pessoa de Meia-Idade , Mitomicina/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: Patients with advanced or metastatic non-gastrointestinal stromal tumour soft tissue sarcoma (STS) whose disease progresses during or after chemotherapy with doxorubicin or ifosfamide have few options and very limited life expectancy. In this setting, the DNA and transcription interacting agent trabectedin (ecteinascidin-743), isolated originally from the tunicate Ecteinascidia turbinata, has encouraging activity and is now approved in the European Union. OBJECTIVE: To review evidence for the efficacy of trabectedin in STSs. METHODS: This review includes material known to the authors through preclinical and clinical work with trabectedin, and information from relevant papers and abstracts. RESULTS: Pooled analysis of Phase II studies suggests that around 50% of STS patients, failing conventional chemotherapy, experienced long lasting tumour control (either objective response or stabilization of disease) when treated with trabectedin. Twenty-nine per cent of patients were alive at 2 years, and median overall survival was 10.3 months. Leiomyosarcomas and liposarcomas appear particularly sensitive to the drug. In myxoid and round-cell liposarcomas trabectedin seems exceptionally active. A link between specific translocations underlying this disease and the drug's mechanism of action is being explored. Trabectedin is also active in synovial, ewing sarcoma and other translocation-related STSs. Trabectedin is not cardio- or neurotoxic. The neutropenia and hepatic toxicity that occur are non-cumulative, reversible, and lessened by steroid premedication. The lack of cumulative toxicities could make trabectedin appropriate for prolonged treatment. CONCLUSION: The potential of trabectedin should be further explored in STSs in general and in specific subtypes, both in combination with other cytotoxic agents and with modulators of intracellular signalling.