RESUMO
OBJECTIVE: Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial. METHOD: Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT)â¯+â¯placebo (P)â¯ââ¯P or CTâ¯+â¯BEVâ¯ââ¯BEV. RESULTS: After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (pâ¯=â¯0.981). There was a non-significant 0.1% (pâ¯=â¯0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (pâ¯=â¯0.890) or VFA (pâ¯=â¯0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (pâ¯=â¯0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (pâ¯=â¯0.606). CONCLUSION: Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor.
Assuntos
Tecido Adiposo/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Adiposidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma Epitelial do Ovário/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/patologia , Obesidade/fisiopatologia , Neoplasias Ovarianas/diagnóstico por imagem , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors. METHODS: Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (>10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC). RESULTS: The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p<0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors. CONCLUSIONS: The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.
Assuntos
Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Neoplasias Peritoneais/mortalidade , Idoso , Ascite/mortalidade , Ascite/patologia , Antígeno Ca-125/metabolismo , Carcinoma Epitelial do Ovário , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasia Residual , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Curva ROC , Estados Unidos/epidemiologiaRESUMO
The Gynecologic Cancer InterGroup (GCIG) Fifth Ovarian Cancer Consensus Conference (OCCC) was held in Tokyo, Japan from 7 to 9 November 2015. It provided international consensus on 15 important questions in 4 topic areas, which were generated in accordance with the mission statement to establish 'International Consensus for Designing Better Clinical Trials'. The methodology for obtaining consensus was previously established and followed during the Fifth OCCC. All 29 clinical trial groups of GCIG participated in program development and deliberations. Draft consensus statements were discussed in topic groups as well as in a plenary forum. The final statements were then presented to all 29 member groups for voting and documentation of the level of consensus. Full consensus was obtained for 11 of the 15 statements with 28/29 groups agreeing to 3 statements, and 27/29 groups agreeing to 1 statement. The high acceptance rate of the statements among trial groups reflects the fact that we share common questions, and recognise important unmet needs that will guide future research in ovarian cancer.
Assuntos
Neoplasias Ovarianas/terapia , Feminino , Humanos , Avaliação das Necessidades , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Epithelial ovarian cancer continues to have the highest case-fatality ratio of all gynecologic cancers, in spite of ongoing advances in risk-assessment, genomics, tumor biology, cytoreductive surgery, chemotherapy, and molecular-targeted interventions. Primary treatment options for advanced-stage disease not only should reflect current best standards, but also need to be tailored for individual patients, with consideration of local resources. METHODS: Formulation of recommendations for optimal primary therapy based on a selective review of data from completed randomized trials, analysis of ongoing trials, and integration with current tumor biology, within the context of individualized clinical care. Recommendations were presented for discussion during an international meeting of experts in ovarian cancer treatment. RESULTS: Key recommendations include full adjuvant therapy for early-stage high-grade serous cancer; tailored utilization of neoadjuvant chemotherapy based on patient comorbidities, extent of disease, and likelihood of achieving optimal surgical cytoreduction; preferred utilization of carboplatin with weekly paclitaxel as primary therapy; consideration of intraperitoneal cisplatin-based therapy in appropriate patients; avoidance of maintenance chemotherapy; lack of necessity for bevacizumab during primary chemotherapy and primary maintenance; acknowledgement of research opportunities and priorities. CONCLUSIONS: Integrated multidisciplinary care, including cytoreductive surgery and platinum-based chemotherapy, remain central to the optimal management of women with advanced-stage ovarian cancer. However, even with recent technical advances, the impact on disease-related mortality is limited, and more attention will be focused on the early integration of research, particularly with neoadjuvant chemotherapy and interval cytoreductive surgery.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Feminino , Humanos , Terapia Neoadjuvante , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Paclitaxel/administração & dosagem , Melhoria de QualidadeRESUMO
Treatment options for patients with high-risk advanced-stage ovarian cancer continue to evolve, including consideration of neoadjuvant chemotherapy (NACT), timing of cytoreductive surgery, utilization of intraperitoneal (IP) chemotherapy, adoption of dose-dense weekly paclitaxel (Taxol), addition of maintenance chemotherapy, and incorporation of bevacizumab. Overall, the proportion of patients with suboptimal residual disease has declined, partly as a result of more aggressive primary surgery, and partly through selection of patients for delayed surgery following NACT. However, the risk of recurrence in this population remains high, and treatment decisions need to be individualized, with consideration of clinical goals, avoidance of treatment-related toxicity, control of disease-related symptoms, and minimization of any negative impact on the quality of life. Innovative trials are needed to evaluate early predictors of primary platinum resistance and facilitate the development of non-platinum alternative treatment regimens.
Assuntos
Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/patologia , Neoplasia Residual/cirurgia , Neoplasias Ovarianas/patologia , Paclitaxel/uso terapêuticoRESUMO
17 T cell clones and 3 T cell lines, specific for pigeon cytochrome c, were analyzed for fine specificity and rearranged T cell receptor (TCR) gene elements. Clones of similar fine specificities were grouped into one of four phenotypes, and correlations between phenotype differences and gene usage could be made. All the lines and clones rearranged a member of the V alpha 2B4 gene family to a limited number of J alpha regions. The beta chain was made up of one of three non-cross-hybridizing V beta regions, each rearranging to only one or two J beta s. The use of alternate V beta regions could be correlated with phenotype differences, which were manifested either as MHC- or MHC and antigen-specificity changes. In addition, the presence of alloreactivity, which defined a phenotype difference, could be correlated solely with the use of an alternate J alpha region. These observations were substantiated by prospective analyses of pigeon cytochrome c-specific T cell lines that were selected for alternate MHC specificity or alloreactivity and were found to express the correlated alpha and beta chain rearrangements. Previously, the TCR DNA sequences from two clones, each representing a variant of one phenotype, showed sequence differences only in the N regions of their TCR genes. Since only these two variants, using identical V alpha-J alpha and V beta-J beta gene elements, were repeatedly observed in this study, we would predict that the junctional diversity differences are selectable. In this T cell response, all the gene elements involved in the generation of diversity appear to be selected, and may therefore be important in the determination of TCR specificity. This high degree of receptor gene selection represents a fundamental difference from the diversity seen in several extensively analyzed antibody responses.
Assuntos
Grupo dos Citocromos c/imunologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Animais , Linhagem Celular , Separação Celular , Células Clonais/imunologia , Columbidae , DNA/genética , DNA Recombinante , Feminino , Complexo Principal de Histocompatibilidade , Masculino , Camundongos , Hibridização de Ácido Nucleico , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/citologiaRESUMO
Advanced-stage epithelial ovarian cancer is generally managed with cytoreductive surgery and chemotherapy consisting of carboplatin and paclitaxel, achieving clinical complete remission in the majority of patients. However, most tumors recur, and are associated with progressive chemotherapy resistance. Techniques to optimize chemotherapy have included intraperitoneal administration and weekly scheduling of paclitaxel. Efforts to improve on the long-term results of primary therapy through addition of a third cytotoxic agent have not been successful, including extended maintenance, as well as strategies to overcome chemotherapy resistance. Limited data emerging from phase III trials using bevacizumab suggest some advantage in progression-free survival, particularly in the maintenance setting, and further data are awaited. At present, primary therapy with carboplatin and paclitaxel remains a well-tolerated standard regimen, including the option of weekly paclitaxel dosing, intraperitoneal delivery and neoadjuvant therapy in selected patients. Emerging biological paradigms will hopefully contribute to individualized treatment options in the future.
Assuntos
Drogas em Investigação/uso terapêutico , Terapia Neoadjuvante/métodos , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Padrão de Cuidado , Calibragem , Carcinoma Epitelial do Ovário , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Terapia Neoadjuvante/normas , Neoplasias Epiteliais e Glandulares/terapia , Neovascularização Patológica/tratamento farmacológico , Neoplasias Ovarianas/terapiaRESUMO
Epithelial ovarian cancer is initially a chemosensitive neoplasm, with overall response rates to systemic platinum-based therapy exceeding 80% in conjunction with cytoreductive surgery. However, long-term survival remains poor due to eventual tumor recurrence and emergence of drug resistance. While platinum (cisplatin or carboplatin) and taxanes remain at the core of primary treatment, there has been increased interest in the evaluation of doublet and triplet combinations with diverse cytotoxic agents, including docetaxel, topotecan, gemcitabine, and PEG-liposomal doxorubicin. This has been prompted by single-agent activity in the setting of recurrent platinum-resistant disease and encouraging data from nonrandomized phase I-II trials. As a result, beginning in 1998, the international cooperative groups collaborated on a series of phase III trials to improve long-term outcomes through the development of new platinum-based combinations. More than 10,000 women have been randomized on these trials, and preliminary data from several studies have been reported. Although final data are pending, there is not currently any evidence to recommend adopting a new two- or three-drug combination, and carboplatin with paclitaxel remains the standard regimen of choice. Rapid developments in molecular-targeted therapy are challenging our paradigm for future clinical trials, and our priorities need to be carefully considered.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Feminino , Humanos , Neoplasias Ovarianas/fisiopatologiaRESUMO
Viable suspensions of human colonic mucosal lymphoid cells have been prepared by sequential treatment of tissue with dithiothreitol, EDTA in calcium- and magnesium-free salt solutions, and purified collagenase. The intestinal lymphocyte population, in comparison with that of peripheral blood, had greater numbers of bone marrow-derived cells, particularly cells bearing membrane IgA; showed spontaneous association with macrophages; underwent rapid rosette formation with sheep erythrocytes; and demonstrated increased in vitro synthesis of immunoglobulin. Total thymus-derived cells were equal in the two populations. Decreases were found in "null" cell numbers, in cells bearing membrane IgD and IgM, and in responsiveness to phytohemagglutinin. Macrophage/monocytes in the intestinal population were increased in size, granularity, motility, sustained glass adherence, and phagocytic activity. Human intestinal lymphoid cells appear to constitute a cell population that is more "mature" and/or "activated", in comparison with the lymphoid cells of peripheral blood. The method of preparation should lend itself to the study of inflammatory bowel disease, gastrointestinal cancer, and the intestinal secretory immune system.
Assuntos
Imunoglobulinas/análise , Mucosa Intestinal/citologia , Linfócitos/imunologia , Proteínas de Membrana/análise , Formação de Anticorpos , Separação Celular/métodos , Colo/citologia , Humanos , Técnicas Imunológicas , Lectinas , Ativação Linfocitária , Microscopia de FluorescênciaRESUMO
Accumulating data suggest that the CD4 T-cell surface antigen transduces an independent intracellular signal during antigen-mediated T-cell activation. CD4 is physically associated with the internal membrane tyrosine protein kinase p56lck and can mediate, after antibody-mediated cross-linking, the rapid enzymatic activation of Lck, implying that CD4 signalling may involve changes in tyrosine protein phosphorylation. In this report, we describe that cross-linking of CD4 results in a series of rapid changes in intracellular tyrosine protein phosphorylation. The most prominent CD4-induced tyrosine phosphorylation change involved p56lck, which became extensively phosphorylated on the carboxy-terminal tyrosine residue 505 and, to a lesser extent, lymphocytes can transduce an intracellular signal resulting in tyrosine protein phosphorylation and strongly suggest that this property of CD4 is mediated through p56lck.
Assuntos
Antígenos Ly/metabolismo , Antígenos CD4/imunologia , Fosfoproteínas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/fisiologia , Linfócitos T/metabolismo , Animais , Antígenos Ly/imunologia , Brometo de Cianogênio , Camundongos , Peso Molecular , Fosfopeptídeos/análise , Fosforilação , Fosfotirosina , Agregação de Receptores/imunologia , Agregação de Receptores/fisiologia , Tirosina/análiseRESUMO
The lymphocyte-specific tyrosine protein kinase p56lck is abundantly expressed in L3T4+ (CD4+) and Lyt-2+ (CD8+) T-lymphocytes, where it is predominantly phosphorylated in vivo on the carboxy-terminal tyrosine residue 505 (Y-505). Upon exposure to activating signals (mitogenic lectins, antibodies to the T-cell receptor), the p56lck expressed in normal cloned murine T-cells is modified into a product which migrates at approximately 59 kilodaltons on sodium dodecyl sulfate-polyacrylamide gels and which possesses several amino-terminal serine phosphorylations. The changes in both mobility and amino-terminal phosphorylation can be reproduced by known activators of protein kinase C (4 alpha-phorbol 12 beta-myristate, dioctanoylglycerol), suggesting that this signal transduction pathway (or related pathways) mediates at least part of these events. Interestingly, agents raising intracellular calcium (such as A23187) cause the appearance of several of these amino-terminal phosphorylation changes but do not cause the pronounced shift in electrophoretic mobility. These data suggest that at least two serine kinase systems are implicated in the alterations of p56lck associated with T-cell activation and that the lck gene product plays a critical role in normal T-cell physiology.
Assuntos
Ativação Linfocitária , Proteínas Tirosina Quinases/metabolismo , Linfócitos T/enzimologia , Animais , Calcimicina/farmacologia , Concanavalina A/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica , Camundongos , Mapeamento de Peptídeos , Fosfoproteínas/metabolismo , Fosforilação , Linfócitos T/classificação , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Diffuse intermediately differentiated lymphocytic lymphoma (IDL) is a rare (approximately 2.5%) histologic subtype of malignant lymphoma. We have reviewed the morphologic, immunophenotypic, and clinical features of this disease in 23 patients treated at the National Cancer Institute in the 25-year period between 1963 and 1988. These tumors are uniformly of B-cell origin, but most of them express the T-cell antigen CD5; lambda light chain was expressed nearly twice as frequently as kappa. Median age at diagnosis was 58 years; all patients presented with stage III or IV disease, and the natural history of disease in these patients was heterogeneous. Median survival of patients was more than 5 years, but those with liver involvement documented by biopsy had a significantly shorter survival. No other prognostic factor or combination of prognostic factors significantly affected survival in this small series; however, patients with high expression of the proliferation-associated nuclear antigen Ki-67, absence of cell-surface antigens CD9 and CD10, and blastic morphology appeared to have poorer survival. Treatment was heterogeneous, but patients who achieved a complete response to combination chemotherapy survived longer than patients who failed to achieve a complete response. Only two patients had complete responses lasting longer than 2 years. Unlike patients with follicular lymphoma, those with relapsed IDL did not undergo histologic progression of the disease to an aggressive lymphoma. However, as with patients with follicular lymphoma, it was possible to observe patients with IDL without therapy for periods up to 5 years. Although a significant minority of patients may have very aggressive disease, it appears that, in most patients, IDL behaves similarly to other lymphomas with indolent histology, and thus, an optimal therapeutic approach has not yet been defined.
Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prednisona/administração & dosagem , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Vincristina/administração & dosagem , Irradiação Corporal TotalRESUMO
Lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) were administered by the ip route to patients with intra-abdominal malignancies. Pharmacokinetic studies of IL-2 revealed 10- to 100-fold higher concentrations of IL-2 in peritoneal fluid versus serum. Ip levels of IL-2 were maintained well above those required to generate and maintain LAK cells in vitro. LAK cell activity was detectable in the peritoneal fluid for the duration of each treatment cycle and did not disappear until IL-2 was discontinued. Detection of interferon-gamma (IFN-gamma) in the peritoneal fluid of all patients was consistent with production in situ by activated lymphocytes. In some patients, low but detectable levels of IFN-gamma were also found in the serum. In vivo activation of monocytes in the peritoneal fluid as measured by in vitro production of hydrogen peroxide was documented in the majority of patients. Neither interleukin-1 nor tumor necrosis factor-alpha was detected in the peritoneal fluid. We found no correlation between the presence or levels of IL-2, IFN-gamma, or LAK cell lytic activity in peritoneal fluid or serum and response or nonresponse to therapy.
Assuntos
Neoplasias Abdominais/terapia , Interleucina-2/administração & dosagem , Células Matadoras Naturais/transplante , Neoplasias Abdominais/imunologia , Líquido Ascítico/imunologia , Humanos , Injeções Intraperitoneais , Interferon gama/metabolismo , Interleucina-2/farmacocinética , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Monócitos/metabolismo , Valor Preditivo dos Testes , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Single-chain Fv proteins containing a COOH-terminal cysteine (sFv') were constructed by using an antidigoxin 26.10 sFv and an anti-c-erbB-2 741F8 sFv. The fully active sFv' proteins were prepared by expression in Escherichia coli as insoluble inclusion bodies, followed by in vitro refolding using glutathione redox buffers and purification. The COOH-terminal cysteines of the refolded sFv' proteins were protected by a blocking group presumed to be the glutathionyl peptide, which was easily and selectively removed by gentle reduction. Air oxidation of the reduced sFv' monomers resulted in the efficient formation of disulfide-linked sFv' homodimers, designated (sFv')2, which were stable under oxidizing conditions and relatively slow to be disrupted under reducing conditions. The (26-10-1 sFv')-(741F8-1 sFv') heterodimer was prepared and possessed dual-antigen specificity; the active bispecific (sFv')2 dimerized under native conditions, apparently as a manifestation of self-association by the 741F8 sFv' subunit. Biodistribution and imaging studies that were performed on mice bearing human SK-OV-3 tumor xenografts that express the c-erbB-2 as a cell surface antigen were reviewed. Radioiodinated 741F8-2 (sFv')2 homodimer localized to the tumors with high specificity, as evidenced by excellent tumor:normal tissue ratios. Sagittal section autoradiography of whole animals 24 h after administration of antibody species revealed that 741F8 (sFv')2 produced a stronger tumor image than comparable doses of the 741F8 Fab, monomeric sFv', and the 26-10 (sFv')2 control without the high nonspecific background distribution of the 741F8 IgG.
Assuntos
Fragmentos de Imunoglobulinas , Radioisótopos do Iodo , Neoplasias/diagnóstico por imagem , Receptor ErbB-2/imunologia , Sequência de Aminoácidos , Animais , Cisteína/química , Cisteína/imunologia , Escherichia coli , Humanos , Fragmentos de Imunoglobulinas/imunologia , Fragmentos de Imunoglobulinas/metabolismo , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Neoplasias/imunologia , Dobramento de Proteína , Cintilografia , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Distribuição Tecidual , Transplante HeterólogoRESUMO
The in vivo properties of monovalent and divalent single-chain Fv (sFv)-based molecules with the specificity of the anti-c-erbB-2 monoclonal antibody 741F8 were examined in scid mice bearing SK-OV-3 tumor xenografts. 741F8 sFv monomers exhibited rapid, biphasic clearance from blood, while a slightly slower clearance was observed with the divalent 741F8 (sFv')2 comprising a pair of 741F8 sFv' with a C-terminal Gly4Cys joined by a disulfide bond. Following i.v. injection, the 741F8 sFv monomer was selectively retained in c-erbB-2-overexpressing SK-OV-3 tumor, with excellent tumor:normal organ ratios uniformly exceeding 10:1 by 24 h. The specificity of this effect was demonstrated by the lack of retention of the anti-digoxin 26-10 sFv monomer, as evaluated by biodistribution studies, gamma camera imaging, and cryomacroautoradiography studies. The specificity index (741F8 sFv retention/26-10 sFv retention) of 741F8 monomer binding, measured by the percentage of injected dose per g of tissue, was 13.2:1 for tumor, and 0.8 to 2.1 for all tested normal organs, with specificity indices for tumor:organ ratios ranging from 7.0 (kidneys) to 16.7 (intestines). Comparing divalent 741F8 (sFv')2 with the 26-10 (sFv')2, similar patterns emerged, with specificity indices for retention in tumor of 16.9 for the Gly4Cys-linked (sFv')2. These data demonstrate that, following their i.v. administration, both monovalent and divalent forms of 741F8 sFv are specifically retained by SK-OV-3 tumors. This antigen-specific binding, in conjunction with the 26-10 sFv controls, precludes the possibility that passive diffusion and pooling in the tumor interstitium contributes significantly to long-term tumor localization. 741F8 (sFv')2 species with peptide spacers exhibited divalent binding and increased retention in tumors as compared with 741F8 sFv monomers. Since the blood retention of the (sFv')2 is slightly more prolonged than that of the monomer, it was necessary to demonstrate that the increased tumor localization of the peptide-linked (sFv')2 was due to its divalent nature. The significantly greater localization of the divalent bismalimidohexane-linked 741F8 (sFv')2 as compared with a monovalent 741F8 Fab fragment of approximately the same size suggests that the increased avidity of the (sFv')2 is a factor in its improved tumor retention. This is the first report of successful specific in vivo targeting of tumors by divalent forms of sFv molecules. The improved retention of specific divalent (sFv')2 by tumors may have important consequences for targeted diagnostic or therapeutic strategies.
Assuntos
Anticorpos Monoclonais/metabolismo , Fragmentos de Imunoglobulinas/metabolismo , Proteínas Proto-Oncogênicas/imunologia , Neoplasias Cutâneas/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/isolamento & purificação , Afinidade de Anticorpos , Especificidade de Anticorpos , Autorradiografia , Epitopos , Espaço Extracelular/metabolismo , Fragmentos de Imunoglobulinas/imunologia , Fragmentos de Imunoglobulinas/isolamento & purificação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Proteínas Proto-Oncogênicas/metabolismo , Cintilografia , Receptor ErbB-2 , Neoplasias Cutâneas/diagnóstico por imagem , Distribuição TecidualRESUMO
PURPOSE: Topotecan, a topoisomerase I inhibitor, was evaluated in a multicenter, phase II study of women with epithelial ovarian carcinoma who relapsed after one or two prior regimens that included platinum and paclitaxel. PATIENTS AND METHODS: Topotecan 1.5 mg/m2 daily was administered as a 30-minute infusion for 5 consecutive days on a 21-day cycle. Eligibility criteria included bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of 2 or less, and adequate bone marrow, liver, and renal function. Efficacy was assessed by independent radiologic review. RESULTS: One hundred thirty-nine patients were treated; 81% were platinum resistant. Sixty-two patients had received one prior regimen and 77 patients had received two prior regimens. Nine patients were not assessable for response; however, all patients were included in the response analysis. The overall response rate was 13.7%; 12.4% in platinum-resistant and 19.2% in platinum-sensitive patients. Stable disease lasted at least 8 weeks in 27.3% of the patients. The median duration of response and time to progression were 18.1 and 12.1 weeks, respectively. The median survival was 47.0 weeks. Grade 4 neutropenia occurred in 82% of the patients (34% of the courses) and thrombocytopenia in 30% of the patients (9% of the courses). Infectious complications occurred in 6% of the courses. Nonhematologic toxicities were mild. There were no drug-related toxic deaths. CONCLUSION: As a single agent, topotecan has modest activity in women with advanced epithelial ovarian carcinoma who have progressed or not responded after one or two prior regimens with platinum and paclitaxel. Further investigation of combination regimens is indicated in the primary therapy for ovarian cancer based on the mechanism of action and tolerability.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Topotecan/uso terapêutico , Adulto , Idoso , Carboplatina/administração & dosagem , Carcinoma/patologia , Cisplatino/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Leucopenia/induzido quimicamente , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neutropenia/induzido quimicamente , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
PURPOSE: Topotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m(2) intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days. RESULTS: Forty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was reported in 15 patients and resulted in the discontinuation of therapy in five responding patients. CONCLUSION: Topotecan is an active drug in platinum-sensitive ovarian cancer, with significant but manageable hematologic toxicity. Fatigue is also a common problem that may be dose-limiting in some patients.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Terapia de Salvação , Topotecan/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Compostos de Platina/farmacologia , Topotecan/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin and paclitaxel with hematopoietic peripheral-blood stem cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with cyclophosphamide, etoposide, and granulocyte-macrophage colony-stimulating factor (GM-CSF). After one cycle of conventional-dose carboplatin and cyclophosphamide with GM-CSF, patients received multiple cycles of high-dose carboplatin (area under the concentration-time curve [AUC], 12 to 20) and paclitaxel (250 mg/m(2)) with PBSC and GM-CSF repeated every 28 days. RESULTS: Twenty-four of 28 patients were assessable for toxicity and clinical outcome. Dose-limiting toxicities were dehydration, diarrhea, and electrolyte imbalances. The maximum-tolerated dose of carboplatin was AUC 16 (equivalent to a median of 1,189 mg/m(2)). The relationship of target AUC to measured AUC was linear (r(2) =. 29; P =.0011). The overall response rate was 96%, with a complete clinical response rate of 67%. The median time to progression from the first PBSC reinfusion was 49.5 weeks (range, 8 to 156+ weeks). CONCLUSION: Multiple cycles of high-dose carboplatin (AUC 16) and paclitaxel (250 mg/m(2)) can be safely administered with GM-CSF and PBSC support. Although this regimen is safe, feasible, and active, the use of multiple cycles of high-dose chemotherapy as front-line treatment remains experimental and should only be used in the context of a clinical trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Terapia Combinada/métodos , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinéticaRESUMO
PURPOSE: We investigated whether carboplatin myelosuppression could be favorably modulated by the administration of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) in patients with advanced-stage ovarian cancer. PATIENTS AND METHODS: Thirty-four patients with advanced-stage recurrent ovarian cancer were treated with high-dose carboplatin (800 mg/m2 per 35-day cycle) and rGM-CSF. rGM-CSF was administered as a daily subcutaneous injection starting 72 hours after the carboplatin dose and continuing until 7 days beyond the WBC nadir. rGM-CSF was administered in a phase I fashion. Seven patients were treated at an rGM-CSF dose of 3 micrograms/kg, 11 at 5 micrograms/kg, 10 at 10 micrograms/kg, and six at 20 micrograms/kg. RESULTS: rGM-CSF-related toxicities that were not dose-related included nonneutropenic fever, rib pain, acute hypersensitivity reaction, and pericarditis. At the rGM-CSF dose of 20 micrograms/kg, debilitating malaise was seen in four of six patients and this was the dose-limiting toxicity. Patient tolerance of the 3-micrograms/kg and 5-micrograms/kg doses was good, but tolerance was limited for the 10-micrograms/kg dose. Febrile neutropenia was seen in four of seven patients at 3 micrograms/kg, two of 11 at 5 micrograms/kg, two of 10 at 10 micrograms/kg, and one of six at 20 micrograms/kg. Cumulative carboplatin myelotoxicity was blunted only in respect to WBC count, and not for platelets or RBCs. Gastrointestinal bleeding was seen in seven patients. The administered dose-intensity of carboplatin averaged 134 mg/m2/wk for the cohort, or 670 mg/m2 per 35-day cycle. There were two clinical complete responses and eleven partial responses, for a response rate of 38%. CONCLUSION: rGM-CSF appears to be effective and tolerable at 5 micrograms/kg/d administered subcutaneously, if given with carboplatin doses up to approximately 600 mg/m2 over 35 days. The use of rGM-CSF with high-dose carboplatin is associated with a substantial response rate in poor-prognosis ovarian cancer patients.
Assuntos
Doenças da Medula Óssea/prevenção & controle , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Transfusão de Sangue , Doenças da Medula Óssea/induzido quimicamente , Doenças da Medula Óssea/terapia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Injeções Subcutâneas , Contagem de Leucócitos/efeitos dos fármacos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , RecidivaRESUMO
OVB3-PE is an immunotoxin composed of a murine monoclonal antibody reactive with human ovarian cancer and conjugated to Pseudomonas exotoxin (PE). Twenty-three patients with refractory ovarian cancer were treated intraperitoneally (IP) with escalating doses of OVB3-PE to study toxicity, pharmacokinetics, antiimmunotoxin antibody formation, and antitumor response. Dose-limiting CNS toxicity occurred after repeated doses at 5 and 10 micrograms/kg. Other non-dose-limiting toxicities included transient elevation of liver enzymes, fever, and gastrointestinal toxicity. Pharmacokinetics of IP and serum OVB3-PE were determined in 16 patients. Peak peritoneal fluid levels exceeded the in vitro median effective dose at all doses tested. At doses of 1 to 2 micrograms/kg, the immunotoxin concentration in the peritoneal fluid remained constant for up to 8 hours and dropped to negligible levels after 12 hours. At the 5 and 10 micrograms/kg doses, levels remained high for up to 24 hours (greater than 100 ng/mL) and then gradually decreased and became undetectable (less than 4 ng/mL) after 72 hours. Serum levels of OVB3-PE were also analyzed in 16 patients. At doses of 1 micrograms/kg and 2 micrograms/kg, serum levels were not detectable (less than 5 ng/mL). However, after doses of 5 or 10 micrograms/kg, peak serum level occurred at 24 hours after each dose and dropped to negligible levels by 72 hours. Sera from 12 patients were analyzed for anti-PE antibodies and antibodies to mouse immunoglobulin (HAMA). All patients developed antibodies against PE within 14 days of therapy. Domain II of PE appeared to be the most immunogenic portion of the PE molecule. HAMA was detected on day 14 of therapy in nine patients, on day 21 in two, and on day 28 in one patient. No clinical antitumor responses were observed. We conclude that IP OVB3-PE at dose levels of 5 micrograms/kg (x 3) and 10 micrograms/kg (x 2) is accompanied by dose-limiting toxic encephalopathy. Neurologic toxicity is likely to be due to crossreactivity of OVB3 to normal human brain tissue, which was not appreciated during preclinical screening.