RESUMO
OBJECTIVE: This study investigated the relationship between 13 proteins involved in DNA damage and the outcomes of patients with recurrent ovarian cancer (ROC). PATIENTS AND METHODS: Immunohistochemistry staining was performed in 114 diagnostic samples from patients with serous ROC who participated in the OVA-301 study, which compared pegylated liposomal doxorubicin (PLD) with a combination of trabectedin plus PLD. Percentage of positive cells for every marker was calculated and correlated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: A statistically significant correlation between high levels of nibrin and lower ORR (P=0.03), shorter PFS (P=0.007) and shorter OS (P=0.01) was observed. After stratification, in patients with platinum-sensitive disease treated with the combination of trabectedin plus PLD, high levels of nibrin correlated with lower ORR (P=0.01) and shorter PFS (P=0.02). A better clinical outcome (ORR, PFS and OS) was also associated to low levels of CHK2 in trabectedin plus PLD treated patients. No correlations were found in PLD-treated patients. According to the results of a multivariate analysis, there was a statistically significant correlation between high nibrin (P=0.001) and low BRCA2 levels (P=0.03) and a worse PFS, and between high nibrin levels and a worse OS (P=0.006). CONCLUSION: Our results indicate that high nibrin expression seems to be associated with a worse clinical outcome in serous ROC, particularly in patients treated with the combination trabectedin plus PLD. Prospective studies to determine clinical usefulness of nibrin as a possible biomarker in other series of patients with ROC are warranted.
Assuntos
Proteínas de Ciclo Celular/análise , Cistadenocarcinoma Seroso/tratamento farmacológico , Proteínas Nucleares/análise , Neoplasias Ovarianas/tratamento farmacológico , Biomarcadores , Cistadenocarcinoma Seroso/química , Cistadenocarcinoma Seroso/mortalidade , Dioxóis/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Neoplasias Ovarianas/química , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Polietilenoglicóis/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tetra-Hidroisoquinolinas/uso terapêutico , Trabectedina , Resultado do TratamentoRESUMO
AIMS: We aimed to evaluate the effect of prior chemotherapies on the outcomes of patients with liposarcoma and leiomyosarcoma treated with trabectedin as a 24-h infusion every 3 weeks. PATIENTS & METHODS: Data from 129 patients who received trabectedin as second-line treatment following failure with an anthracycline/ifosfamide and those who had received at least two lines of prior chemotherapy were analyzed. RESULTS: Forty seven patients received one prior regimen (group A) and 82 patients received at least two lines of chemotherapy (group B). A favorable trend in median time to progression (4.4 vs 3.0 months), progression-free survival (4.4 vs 2.6 months) and overall survival (17.4 vs 13.3 months) was found in group A. A trend toward higher overall response rate (6.4 vs 4.9%) and disease control rate (34.0 vs 26.8%) also favored group A. Both groups had equivalent safety profiles. CONCLUSION: All efficacy outcomes were better in patients who received trabectedin as second-line treatment compared with patients with more extensive prior therapy.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Lipossarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Leiomiossarcoma/mortalidade , Leiomiossarcoma/patologia , Lipossarcoma/mortalidade , Lipossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Resultado do TratamentoRESUMO
PURPOSE: This study assesses the efficacy, toxicity and pharmacokinetic profile of trabectedin with or without prophylactic dexamethasone co-treatment in patients with recurrent advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: Patients were randomized to receive trabectedin as a 3-h infusion every 3 weeks with dexamethasone or placebo in the first cycle, with the alternate in the second cycle and with the patient's choice subsequently. Due to toxicity, the randomized design was modified to open-label to make dexamethasone mandatory and the initial dose (1,650 µg/m(2)) was reduced to 1,500 µg/m(2) and then to 1,300 µg/m(2). RESULTS: Forty-one patients were enrolled and 35 were evaluable for efficacy. One partial response and 18 disease stabilizations were found. The median PFS and OS were 2.1 and 10.2 months, respectively, with the 3- and 6-month PFS rates indicating activity in pretreated STS. Twenty-three and 27 patients developed transient asymptomatic grade 3/4 AST and ALT elevation, respectively, and 21 patients had grade 3/4 neutropenia. Dose reduction from 1,650 µg/m(2) to 1,300 µg/m(2) decreased the incidence of grade 3/4 thrombocytopenia (26% vs. 0%), neutropenia (51% vs. 25%) and AST increase (76% vs. 25% of patients). Four patients died due to drug-related toxicities (3 with placebo). The total body clearance of trabectedin was 28% higher and half-life was 21% lower with dexamethasone compared to placebo, with no differences in volume of distribution. CONCLUSIONS: Trabectedin has confirmed activity in patients with pretreated STS. This study shows that co-treatment with dexamethasone improves the safety of trabectedin by reducing drug-induced hepatotoxicity and myelosuppression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Dexametasona/administração & dosagem , Dioxóis/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Sarcoma/secundário , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Espanha , Tetra-Hidroisoquinolinas/administração & dosagem , Trabectedina , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n = 13) or limited-stage disease (n = 7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.
Assuntos
Antineoplásicos/administração & dosagem , Depsipeptídeos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/secundário , Adulto , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Feminino , Humanos , Infusões Intravenosas , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Peptídeos Cíclicos , Prognóstico , Terapia de Salvação , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/secundário , Carcinoma de Pequenas Células do Pulmão/secundário , Taxa de Sobrevida , Resultado do TratamentoRESUMO
AIM: To evaluate motoric intestinal disturbances during inflammation with Trichinella spiralis in rats as an experimental model. METHODS: We examined the changes in worm-positive (jejunum) and worm-free (ileum) intestinal segments of rats infected with T. spiralis. To investigate the relationship between structural and functional changes in smooth muscle, we measured the thickness of the muscle layers of rat jejunum and ileum. Mechanical responses to KCl 30 mmol/L, acetylcholine (ACh) 10(-8)-10(-4) mol/L, substance P (SP) 10(-9)-10(-5) mol/L, and to electrical field stimulation of longitudinal muscle strips in the jejunum and ileum were studied in muscle bath as controls (day 0) and on day 2, 6, 14, 23, and 72 after infection. RESULTS: After T. spiralis infestation, an inflammation of the mucosal and submucosal layers of jejunum was observed, whereas in the worm-free ileum there was not any inflammatory infiltrate. Increase in the smooth muscle thickness of both jejunum and ileum were correlated with increased responses to depolarizing agent KCl and to ACh. However, responses to SP were decreased on day 14-23 after infection in jejunum and from day 6-14 after infection in ileum. Electric field stimulation-induced contractions were transiently decreased in the jejunum (day 2 after infection) but in the ileum the contractile responses were decreased until the end of the study period. CONCLUSIONS: Alterations in intestinal smooth muscle function do not require the presence of the parasite and the absence of histopathological signs of inflammation do not warrant intact motor function. Changes in motor responses after T. spiralis infection are not only due to smooth muscle damage but also to disturbances in specific receptor-mediated mechanisms.
Assuntos
Intestino Delgado/fisiopatologia , Contração Muscular , Músculo Liso/fisiopatologia , Trichinella spiralis , Triquinelose/fisiopatologia , Acetilcolina/farmacologia , Animais , Estimulação Elétrica , Motilidade Gastrointestinal , Técnicas In Vitro , Inflamação , Intestino Delgado/parasitologia , Intestino Delgado/patologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/patologia , Neurotransmissores/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Substância P/farmacologia , Triquinelose/parasitologia , Triquinelose/patologiaRESUMO
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Neoplasias da Mama/tratamento farmacológico , Dioxóis/uso terapêutico , Síndrome Hereditária de Câncer de Mama e Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias da Mama/genética , Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Neoplasias Ovarianas/genética , Polietilenoglicóis/administração & dosagem , Sarcoma/genética , Tetra-Hidroisoquinolinas/administração & dosagem , TrabectedinaRESUMO
Functional motor changes and morphological alterations have been associated with intestinal inflammation. The aim of this work was to study functional motor changes in inflamed and non-inflamed intestinal segments of Trichinella spiralis infected rats. Thickness of muscle layers and cell infiltration during infection were also evaluated. Segments of rat jejunum and ileum were placed in organ bath and relaxations of the longitudinal muscle in response to electrical field stimulation (EFS) were recorded. During the post-infection (PI) period EFS-induced relaxations in ileum were decreased. Maximal decreases in relaxation were found on day 14-23 PI for ileum, whereas non significant changes were observed in jejunal samples throughout the experimental period. The sensitivity of the EFS-induced relaxations to the NO synthase inhibitor Nomega-nitro-L-arginine (L-NNA) and to the soluble guanylate cyclase inhibitor oxadiazolo-quinoxalin-1-one (ODQ) was decreased on day 14 PI for jejunum, whereas in the ileum it lasted from day 14-23 PI. The sensitivity of EFS-induced relaxations to apamin (a small conductance calcium activated potassium channel blocker) disappeared between day 6-23 PI for both jejunum and ileum. In contrast, the sensitivity of the EFS-induced relaxations to the K(+) channel blockers tetraethylamonium (TEA) and tetrapenthylammonium (TPEA) chloride was similar for healthy tissue and for tissue obtained form infected animals. Distribution and density of NADPH-diaphorase positive neurons was similar in tissue obtained form healthy and infected animals. In conclusion, intestinal inflammation induces functional and structural changes in both worm-free and worm-positive intestinal segments. Increased muscle thickness was similar for both inflamed and noninflamed segments but the most prominent functional changes i.e. a long-lasting decrease of EFS-induced relaxation was found in non-inflamed ileal segments.
Assuntos
Íleo/fisiopatologia , Jejuno/fisiopatologia , Músculo Liso/fisiopatologia , Triquinelose/fisiopatologia , Animais , Estimulação Elétrica , Campos Eletromagnéticos , Íleo/parasitologia , Jejuno/parasitologia , Masculino , Contração Muscular , Músculo Liso/parasitologia , Ratos , Ratos Sprague-Dawley , Trichinella spiralisRESUMO
Trabectedin (ET-743, Yondelis®) is a novel marine antineoplastic alkaloid with a unique mechanism of action. The active substance trabectedin, a tetrahydroisoquinoline alkaloid, is a natural product originally isolated from the Caribbean sea squirt, Ecteinascidia turbinata and is currently manufactured by total synthesis. Trabectedin is licensed by the Spanish pharmaceutical drug company, PharmaMar and co-developed by Johnson & Johnson Pharmaceutical Research and Development, L.L.C., pursuant to a licensing agreement with PharmaMar. Trabectedin is the first anticancer marine-derived drug to be approved by the European Union. In 2007, trabectedin obtained marketing authorization from the European Commission and in many other countries worldwide for the treatment of patients with advanced soft tissue sarcoma (STS) after failure of anthracyclines and ifosfamide, or for those patients who are unsuitable to receive these agents. Based on the recently reported results of a large phase III study (OVA-301) comparing pegylated liposomal doxorubicin (PLD) alone with a combination of PLD and trabectedin in patients with recurrent ovarian cancer, in 2009 the European Commission granted marketing authorization for trabectedin combined with PLD for the treatment of patients with relapsed platinum-sensitive ovarian cancer. The results from OVA-301 showed that the combination of trabectedin and PLD improves progression-free survival and overall response rate over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer. In addition, an enhanced activity of trabectedin combined with PLD was observed in platinum sensitive patients, especially in those with a platinum-free interval ranging from 6 to 12 months. Overall, trabectedin-induced toxicities are mainly hematological and hepatic, with grade 3/4 neutropenia and thrombocytopenia observed in approximately 50% and 13% of patients, respectively, and grade 3/4 elevation of liver aminotransferases observed in 40-50% of patients treated with trabectedin. Current efforts are focused on the evaluation of the role of trabectedin in prolonging the platinum-free interval and the identification of predictive factors for patients treated with trabectedin as well as in the development of new trabectedin-based combinations.
Assuntos
Antineoplásicos/uso terapêutico , Dioxóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Feminino , Humanos , Recidiva , TrabectedinaRESUMO
This phase II clinical trial evaluated the antitumour response of Kahalalide F (KF) 650 microg/m(2) given as a 1-h weekly infusion in advanced malignant melanoma patients, both untreated and those who relapsed or progressed after one line of systemic therapy. Of 24 enrolled patients (median age, 55 years; range, 28-89), 14 patients had been previously treated with chemotherapy or biological therapy. No RECIST responses occurred; five chemotherapy-naïve patients with cutaneous melanoma had disease stabilisation for > or = 3 months; median progression-free survival was 1.7 months (95% CI, 1.2-1.9 months); and median overall survival was 10.8 months (95% CI, 5.0-upper limit not reached). The most common laboratory toxicities were non-cumulative increase of transaminases (ALT/AST) and gamma-glutamyltransferase (GGT). No patients experienced leukopenia and thrombocytopenia during the study. KF was a well-tolerated and safe chemotherapy regimen. Despite a favourable safety profile, this trial was closed after the first stage because of the lack of objective response in patients with malignant melanoma.
Assuntos
Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Depsipeptídeos/efeitos adversos , Depsipeptídeos/sangue , Feminino , Humanos , Masculino , Melanoma/sangue , Melanoma/patologia , Melanoma/secundário , Pessoa de Meia-Idade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Gefitinib (Iressa) is a novel drug approved in 28 countries (as of June 2004), including Japan, the US, Canada and Australia as second- and third-line monotherapy for the treatment of locally advanced or metastatic non-small cell lung cancer refractory to prior chemotherapy. Gefitinib is an orally active, epidermal growth factor receptor (EGFR)-tyrosine kinase (EGFR-TK) reversible inhibitor which blocks EGFR phosphorylation and subsequent signal transduction pathways involved in proliferation, metastasis, angiogenesis and apoptosis inhibition. Recently, mutations in the TK domain of the EGFR have been identified in those patients with refractory non-small cell lung cancer who achieved dramatic tumor responses to gefitinib. Although the role of EGFR-TK mutation status in predicting other clinical benefits with gefitinib, i.e. disease stabilization and symptom improvement, is unclear, these findings, along with increasing knowledge of other potential biomarkers of response, are significant developments towards further optimizing the use of gefitinib. Gefitinib has favorable pharmacokinetic and pharmacodynamic properties and low toxicity. No dosage adjustment is required for patient age, body weight, gender, ethnicity or moderate to severe hepatic impairment due to liver metastases. Several clinical studies on gefitinib as monotherapy have demonstrated clinically significant symptom relief, tumor response and good tolerability after failure of chemotherapy-based treatment in non-small cell lung cancer. These studies led to gefitinib approval in many countries as a new therapeutic option for patients with advanced non-small cell lung cancer that failed prior chemotherapy. In contrast to the clinical benefit imparted by gefitinib as monotherapy in patients previously treated with chemotherapy, gefitinib in combination with standard platinum-based chemotherapy in chemonaive patients did not improve either survival or other clinical endpoints in non-small cell lung cancer. This review provides currently available data from clinical studies on gefitinib as monotherapy or in combination with platinum-containing chemotherapy.