RESUMO
BACKGROUND: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). METHODS: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. RESULTS: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). CONCLUSIONS: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Fitogênicos/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/farmacologia , Intervalo Livre de ProgressãoRESUMO
OBJECTIVES: Vascular endothelial growth factors (VEGF) and their receptors have a critical role in stimulating the growth of ovarian cancer cells. Motesanib is a small molecule inhibitor of multiple receptor tyrosine kinases including VEGF receptors 1-3, as well as c-KIT and platelet-derived growth factor which are related to the VEGF family. PATIENTS AND METHODS: Twenty-two eligible patients with recurrent ovarian, fallopian tube or primary peritoneal carcinoma were treated with an oral daily dose of 125 mg of motesanib. Peripheral blood was analyzed for circulating tumor cells (CTC) and circulating endothelial cells/circulating endothelial progenitors (CEC/CEP), VEGF levels and cell-free circulating DNA (cfDNA). RESULTS: The study was abruptly halted after four patients developed posterior reversible encephalopathy syndrome. One patient had a partial response and seven patients had stable disease at the time they were removed from study treatment. Twelve of the 22 patients (50%) had indeterminate responses at trial closure. Early closure without clinical efficacy data precludes meaningful correlative studies. CONCLUSIONS: The serious central nervous system toxicity observed in patients with recurrent ovarian cancer precluded full examination of this agent in this population. There were no clear cut explanations for the high incidence of this known class effect in the study population compared with patients with other cancers.
Assuntos
Neoplasias das Tubas Uterinas/tratamento farmacológico , Indóis/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Niacinamida/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , DNA de Neoplasias/análise , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Humanos , Indóis/efeitos adversos , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Oligonucleotídeos , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies. PATIENTS AND METHODS: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m(2), and normal cardiac function. A 1-h PLD (30 mg/m(2)) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m(2)) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles. RESULTS: The MTD of trabectedin was 1.1 mg/m(2). Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent. CONCLUSION: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Dioxóis/sangue , Dioxóis/farmacocinética , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/sangue , Tetra-Hidroisoquinolinas/farmacocinética , TrabectedinaRESUMO
In an attempt to magnify differences in the immune responses of potentially immunosuppressed cancer patients and normal controls, an assessment was made on the effects of the competitive inhibitor alpha-methyl-D-mannoside on the concanavalin A (Con A)-induced blastogenic responses of lymphocytes from each of these populations. Lymphocytes from breast cancer patients with metastatic disease were significantly deficient in their capability to undergo blast transformation regardless of whether the monosaccharide inhibitor was added to the assay cultures. In contrast, lymphocytes from breast cancer patients who did not display metastatic disease were capable of normal blastogenic responses to Con A. The addition of alpha-methyl-D-mannoside to lymphocyte cultures caused a significantly greater inhibition of the blastogenic responses of these patients' cells as compared to cells of normal controls. Thus the monosaccharide seems to serve as a useful reagent for optimizing differences between lymphocyte blastogenic responses of normal donors and those of immunodepressed donors. The results suggest that lymphocytes from breast cancer patients without clinically evident metastases possess some modification of their cell membrane. One possibility discussed was that the number or distribution of receptors for Con A on the membrane of lymphocytes of these patients is deficient.
Assuntos
Neoplasias da Mama/imunologia , Concanavalina A/antagonistas & inibidores , Linfócitos/efeitos dos fármacos , Metilglicosídeos/farmacologia , Metilmanosídeos/farmacologia , Ligação Competitiva , Neoplasias da Mama/patologia , Membrana Celular/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/imunologia , Pessoa de Meia-Idade , Metástase Neoplásica , Receptores de Concanavalina A/efeitos dos fármacos , Receptores de Concanavalina A/metabolismoRESUMO
Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior chemotherapy, and the median performance status was 1. Nausea/vomiting (> or = grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m2 were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Compostos Organoplatínicos/farmacocinética , Compostos Organoplatínicos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Condução Nervosa/efeitos dos fármacos , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ultrafiltração , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Development of biological and clinical uses of in vivo 31P magnetic resonance spectroscopy has been hampered by poor anatomic localization of spectra and poor resolution of overlapping signals within phosphomonoester and phosphodiester regions of the spectrum. We applied 1H-decoupling and nuclear Overhauser enhancement to improve resolution of 31P magnetic resonance spectra accurately localized to 21 non-Hodgkin's lymphomas (NHL) by using three-dimensional chemical shift imaging. All 21 spectra had large phosphomonoester signals (26% of total phosphorus) that contained high amounts of phosphoethanolamine relative to phosphocholine. There were no signals from glycerophosphoethanolamine or glycerophosphocholine but only a broad signal from membrane phospholipids in the phosphodiester region (20% of phosphorus). Prominent nucleoside triphosphates (47% of phosphorus) and low inorganic phosphate (7% of phosphorus) indicate well-perfused tissue with viable cells. Mean intracellular pH was 7.23. These characteristics were similar in all grades and stages of NHL. By analogy with recently reported studies in cell lines in vitro, we hypothesize that the pattern of phospholipid metabolites observed in NHL in vivo is partly a manifestation of sustained activation of phospholipase C or D. The techniques we implemented permitted us to obtain more information about in vivo metabolism of NHL than has heretofore been available. This information is important for the establishment of appropriate experimental models and provides a basis from which to examine potential clinical uses of 31P magnetic resonance spectroscopy.
Assuntos
Linfoma não Hodgkin/metabolismo , 2,3-Difosfoglicerato , Adulto , Idoso , Difosfatos/metabolismo , Ácidos Difosfoglicéricos/metabolismo , Ésteres/metabolismo , Etanolaminas/metabolismo , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fosfatidiletanolaminas/metabolismo , Fosfocreatina/metabolismo , Fosforilcolina/metabolismoRESUMO
PURPOSE: The aim of this study was to determine the maximum-tolerated dose (MTD) of cyclophosphamide, doxorubicin, etoposide, prednisone, bleomycin, cytarabine, methotrexate, and leucovorin (ProMACE-CytaBOM) when the myelotoxic drugs cyclophosphamide, doxorubicin, etoposide, and cytarabine are escalated. PATIENTS AND METHODS: Thirty-eight eligible patients with diffuse aggressive non-Hodgkin's lymphoma were treated on a phase I trial of dose escalation using the ProMACE-CytaBOM regimen and granulocyte-macrophage colony-stimulating factor (GM-CSF; Schering, Kenilworth, NJ). Patients were treated with recombinant (r)GM-CSF 10 microg/kg/d subcutaneously from day 9 to 19. Twenty-seven patients had stage IV disease, four had stage III, and seven had bulky stage II. Half of the patients had bone marrow involvement. The median age was 45 years. RESULTS: We found that the MTD was 200% for the escalated drugs in this regimen (although we never escalated above the MTD or defined by dose-limiting toxicity) and that the normalized dose-intensity (NDI; defined as the ratio of the received dose-intensity to the 100% dose-intensity of ProcMACE-CytaBOM) decreased with each cycle and was lower for the day-8 drug (cytarabine) than for the day-1 drugs. The complete response (CR) rate was 66%, and 92% of patients who achieved CR are alive without disease with a median follow-up time for survival of 3.6 years. CONCLUSION: The MTD of cyclophosphamide, doxorubicin, etoposide, and cytarabine in the ProMACE-CytaBOM regimen given with growth factor support is 200%, and this dose should be tested in larger phase II trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Etoposídeo/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
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: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias dos Genitais Femininos/tratamento farmacológico , Adulto , Idoso , Medula Óssea/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Coração/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Nervos Periféricos/efeitos dos fármacosRESUMO
PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin, paclitaxel, and topotecan with 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 either filgrastim alone or in combination with cyclophosphamide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m(2)), and topotecan (10-15 mg/m(2)), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days. RESULTS: Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m(2) when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m(2). The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded. CONCLUSION: Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m(2), and topotecan 10 mg/m(2). Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Paclitaxel/administração & dosagem , Topotecan/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicação , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Estomatite/induzido quimicamenteRESUMO
PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20(+) B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass > or = 5 cm. RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/microL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (> or = 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody). CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma não Hodgkin/radioterapia , Adolescente , Adulto , Anticorpos Monoclonais Murinos , Antígenos CD20/efeitos dos fármacos , Antígenos CD20/imunologia , Linfócitos B/patologia , Feminino , Humanos , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Radioimunoterapia , Recidiva , Rituximab , Radioisótopos de Ítrio/uso terapêuticoRESUMO
PURPOSE: A phase I and pharmacologic study to evaluate the feasibility of administering paclitaxel (PTX) in combination with topotecan (TPT) without and with granulocyte colony-stimulating factor (G-CSF) in women with recurrent or refractory ovarian cancer. PATIENTS AND METHODS: TPT was administered as a 30-minute infusion daily for 5 days and PTX was given as a 24-hour infusion (PTX-24) either before TPT on day 1 or after TPT on day 5. Each patient received both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or PTX-24 without and with G-CSF resulted in five dosage permutations of TPT/PTX (mg/ m2): 0.75/135 without G-CSF and 0.75/135, 1.25/135, 1.50/135, and 1.25/170 with G-CSF. RESULTS: Twenty-two patients received 109 courses of therapy. Dose-limiting myelosuppression consistently occurred at the first TPT/PTX-24 dose level (0.75/135 mg/m2) in the absence of G-CSF support. Although the addition of G-CSF resulted in reduced rates of complicated neutropenia, the incidences of dose-limiting neutropenia and thrombocytopenia were unacceptably high after the doses of either TPT or PTX-24 were increased. Paired analysis showed similar hematologic toxicities between the two sequences of drug administration. The pharmacologic behavior of both TPT and PTX-24 was not altered by drug sequencing. Major antitumor responses occurred in 40% of patients with measurable and assessable disease, including 45% and 9% of patients with potentially cisplatin-sensitive and -resistant tumors, respectively. CONCLUSION: The recommended doses of TPT on a daily times-five schedule combined with PTX-24 in these patients were 0.75 mg/m2/d and 135 mg/m2, respectively, with G-CSF support. Although this dose of PTX has significant single-agent activity in ovarian cancer, the dose of TPT is much lower than the TPT dose at which single-agent activity has been observed. Due to the inability to administer near relevant single-agent doses of both drugs in combination, as well as the requirement for G-CSF support, further evaluations of this regimen in women with refractory or recurrent ovarian cancer are necessary before it can be recommended for previously treated patients in this setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Trombocitopenia/induzido quimicamente , Topotecan , Vômito/induzido quimicamenteRESUMO
Etoposide phophate is a phosphate ester prodrug of etoposide designed to improve the pharmaceutical characteristics of the parent compound. A Phase I dose-escalating study of etoposide phosphate was conducted concurrently at two institutions to determine its toxicity, pharmacokinetics, and maximum tolerated dose. Etoposide phosphate was administered i.v. for 30 min on days 1, 3, and 5 every 21 days or on recovery from toxicity. Cohorts of at least three patients received etoposide phosphate at dose levels from 50 mg/m2 to 150 mg/m2 expressed as molar equivalents of etoposide. Blood and urine samples were obtained from all patients during the first cycle of treatment and the concentrations of etoposide phosphate and etoposide were measured. Thirty-nine patients with documented cancers received a total of 75 cycles of etoposide phosphate. The dose-limiting toxicity was myelosuppression which occurred at the 150-mg/m2 etoposide equivalent dose. Etoposide phosphate was rapidly and extensively converted to etoposide. No measurable etoposide phosphate was detectable in the plasma by 15-60 min after the end of the infusion. The mean half-life of etoposide at the different dose levels ranged from 5.5 to 9.3 h. The pharmacokinetics of etoposide, generated from etoposide phosphate, was linear over the dose range studied and was comparable to results reported in the literature for i.v. etoposide. In summary, i.v. etoposide phosphate is rapidly and extensively converted to etoposide. The maximum tolerated dose of etoposide phosphate when given on days 1, 3, and 5 is 150 mg/m2/day. The dose-limiting toxicity is myelosuppression. The maximum tolerated dose and adverse event profile are consistent with those of etoposide.
Assuntos
Antineoplásicos/efeitos adversos , Etoposídeo/análogos & derivados , Neoplasias/tratamento farmacológico , Compostos Organofosforados/efeitos adversos , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/farmacocinética , Feminino , Meia-Vida , Hemoglobinas/análise , Humanos , Infusões Intravenosas , Leucopenia/induzido quimicamente , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/sangue , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/farmacocinética , Trombocitopenia/induzido quimicamenteRESUMO
Approximately 55,400 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year, with the overall prevalence of the disease now estimated to be 243,000. Until recently, treatment alternatives for advanced disease included chemotherapy with or without external beam radiation. Based on the results of several clinical trials, the chimeric monoclonal antibody Rituximab has now been approved by the United States Food and Drug Administration as a treatment for patients with relapsed or refractory, low-grade or follicular, B-cell NHL. Several other monoclonal antibodies in conjugated and unconjugated forms have been evaluated in the treatment of NHL. Ibritumomab, the murine counterpart to Rituximab, radiolabeled with 90Y (Zevalin), is presently being evaluated in clinical trials. The success of radioimmunotherapy is dependent upon the appropriate choice of antibody, isotope, and chelator-linker. The Ibritumomab antibody targets the CD20 antigen. The antibody is covalently bound to the chelator-linker tiuxetan (MX-DTPA), which tightly chelates the isotope 90Y. To date, two Phase I/II Zevalin clinical trials have been completed in patients with low-grade, intermediate-grade, and mantle cell NHL. The overall response rate was 64% in the first trial and 67% in the later trial. Phase II and III trials are ongoing.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Linfoma não Hodgkin/radioterapia , Radioimunoterapia , Radioisótopos de Ítrio/uso terapêutico , Humanos , Ácido Pentético , RecidivaRESUMO
Recent advances in hematopoietic support have extended the application of high-dose chemotherapy in the treatment of malignancy. The use of colony-stimulating factors and peripheral blood progenitor cells significantly have decreased the morbidity and mortality of such treatment compared with traditional autologous bone marrow transplantation. These innovations facilitate the use of multiple cycles of high-dose chemotherapy as consolidation after achieving best response to conventional chemotherapy or as initial treatment. Developing data suggest that this approach in both of these settings merit further evaluation for the treatment of epithelial ovarian carcinoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores Estimuladores de Colônias/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Esquema de Medicação , Feminino , HumanosRESUMO
The combination of carboplatin and paclitaxel is an active regimen in non-small cell lung cancer (NSCLC). Historically, patients with stage III disease have manifested higher response rates than patients with metastatic disease, and patients achieving a pathologic complete response to induction chemoradiation therapy prior to surgery have shown better long-term outcome. Based upon our pilot data using high-dose carboplatin and paclitaxel, we designed a phase II trial in patients with marginally resectable stage IIIA NSCLC. Ten patients, with bulky nodal stage IIIA disease, initially received etoposide (2 g/m2) and granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells (PBSC). Two cycles, 28 days apart, of carboplatin (AUC 12 in seven patients; AUC 16 in three patients) and paclitaxel (250 mg/m2) were administered with filgrastim (5 microg/kg) and PBSC support. After re-evaluation, patients underwent a thoracotomy followed by radiotherapy (44-60 Gy) if deemed resectable, or radiotherapy alone (60 Gy) if not resectable. The median age was 58.5 years (48-66) with a median ECOG performance status of 0 (0-1). Histology was adenocarcinoma in seven patients; the remainder had either squamous cell, large cell or bronchoalveolar carcinoma. Based on CT radiography, the overall response rate was 40%. Eight of ten patients underwent resection with four right pneumonectomies, three right upper lobectomies and one wedge resection of the right upper lobe. Six patients had a complete resection. Of eight patients resected, four were downstaged by induction therapy, three remained unchanged and one was found to have more extensive disease. The remaining two patients developed metastatic disease while receiving chemotherapy. The median dose of postoperative radiotherapy was 54 Gy (35-66 Gy). Actual median follow-up for all patients was 89 weeks (25 to 136+). The actuarial median overall survival was 124 weeks (25 to 136+) and time to progression was 57 weeks (17 to 136+). The median dose of carboplatin delivered expressed as mg/m2 was 779 (615-1540). Neutropenic fever occurred in two patients during the initial mobilization cycle only. The median number of units of RBC and/or platelets transfused was 0 (0-2 and 0-6, respectively). There were no significant non-hematologic toxicities. High-dose induction chemotherapy with stem cell rescue is feasible and safe with an acceptable response rate. Thoracotomy, including pneumonectomy and postoperative radiotherapy, were well tolerated by patients after undergoing high-dose induction chemotherapy with no apparent increase in peri-operative morbidity. The pathologic complete response rate was low--one out of ten patients. These results indicate that dose escalation of induction chemotherapy does not improve response rates even in this highly selected patient population. Accordingly, the complexity and potential toxicity of high-dose chemotherapy, as delivered in this trial as neoadjuvant treatment of non-small cell lung cancer, is not warranted.
Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/terapia , Transplante de Células-Tronco Hematopoéticas , Neoplasias Pulmonares/terapia , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Toracotomia , Resultado do TratamentoRESUMO
Approximately 30% of patients with epithelial ovarian cancer present with localized or early-stage disease. Accuracy of staging is dependent on careful surgical staging. Subsets of patients with specific prognostic factors have now been identified who do not require additional therapy after proper primary surgical staging. Poor prognosis patients do require adjuvant therapy. Whole abdominal irradiation, intraperitoneal P32, and single agent and combination chemotherapy have been utilized. The optimal therapy or whether any therapy is truly effective remains unknown.
Assuntos
Neoplasias Ovarianas/terapia , Carcinoma/terapia , Quimioterapia Adjuvante , Terapia Combinada , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologiaRESUMO
Approximately one third of patients with epithelial ovarian cancer present with localized or early-stage disease. Prognostic features identify certain subsets of patients with good risk characteristics who do not require adjuvant treatment after comprehensive surgical staging and cytoreduction. Only a minority of patients undergo such a complete procedure, which often results in understaging of these patients. In the United States, patients with poor prognostic features, such as stage IC to II disease, poorly differentiated histologic grade, clear cell histology, dense adhesions, and large volume ascites, have received adjuvant chemotherapy. Single-agent or combination chemotherapy, whole abdominal irradiation, and intraperitoneal phosphorus 32 have been evaluated, although no modality has been shown to improve overall survival. Randomized trials investigating the optimal therapy or whether any therapy is truly effective are in progress. Until the completion of these trials, the most common postoperative adjuvant therapy in these patients in this country remains combination chemotherapy.
Assuntos
Neoplasias Ovarianas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/fisiopatologia , Neoplasias Ovarianas/terapia , Prognóstico , Taxa de SobrevidaRESUMO
No new publication appeared in the past year on early stage ovarian cancer. The current GOG study will help determine the relative benefits and toxicities of intraperitoneal P32 versus cyclophosphamide and cisplatin in this group of patients. Recent studies in advanced ovarian carcinoma suggest a modest additional benefit for multidrug regimens, but cisplatin and cyclophosphamide remains an acceptable first line treatment for stage III and IV disease. Additional information on the use of carboplatin in advanced disease has been published, and this agent is now accepted as part of standard first line treatment programs. Platinum-based chemotherapy continues to be the mainstay of treatment for recurrent disease. With the commercial availability of taxol, a new salvage treatment is now available. Taxol will be increasingly studied as a part of front-line therapy as well as its role in the salvage setting. Altretamine and ifosfamide appear to have activity even in some patients with platinum-resistant disease, but these drugs will not likely have a major impact on ovarian cancer treatment. The use of high-dose chemotherapy with autologous bone marrow or peripheral stem cell support offers an exciting and potentially beneficial approach for patients with poor prognosis disease. The use of intraperitoneal chemotherapy and biologic agents continues to be problematic, and additional improvements are needed before they are considered useful outside of a research setting. With the exception of P32 for early stage disease, radiation therapy is likely to continue to play a minor role in the treatment of ovarian cancer. Few studies involving non-epithelial ovarian carcinomas were published during the past year. A definitive report was published demonstrating the activity of cisplatin-based chemotherapy (BEP) in patients with advanced dysgerminoma. Chemotherapy which preserves fertility provides an effective alternative to irradiation. Cisplatin-based chemotherapy was active in mixed mullerian tumors of the ovary although the prognosis of these patients was worse than patients with epithelial ovarian cancer. Concurrent chemotherapy added to irradiation has not improved survival over radiotherapy alone in patients with cancer of the uterine cervix. Patients still failed locally and distantly. Extended field irradiation to involved paraaortic lymph nodes with weekly cisplatin generated promising pilot data. Randomized trials evaluating the use of neoadjuvant chemotherapy prior to pelvic radiotherapy showed no benefit and increased toxicity. Ifosfamide alone or in combination regimens is an active drug but with serious side effects which require careful monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Neoplasias dos Genitais Femininos/terapia , Terapia Combinada , Neoplasias do Endométrio/terapia , Feminino , Neoplasias dos Genitais Femininos/patologia , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias do Colo do Útero/terapiaRESUMO
A large study of tumors of low malignant potential confirmed the favorable survival in this group of patients compared to invasive epithelial ovarian tumors. Only 8% of patients died with recurrent disease after surgery. Patients with stage IA borderline tumors with mucinous histology tended to recur later and carried a poorer prognosis than patients with serous histology and similar stage. The group at highest risk for relapse were age greater than 70, stage II or III tumors, and histology other than serous. Long-term survival in this group was less than 75%. This high-risk group of patients should be targeted for innovative adjuvant treatment strategies. This year several well-designed studies with large sample sizes showed DNA ploidy to be an important new independent prognostic factor in stage I ovarian carcinoma. In patients with well-differentiated early stage ovarian cancer, DNA flow cytometric analysis may indicate subgroups with less favorable prognostic characteristics. This method of analysis may be beneficial in determining the need for additional treatments after surgery for early stage ovarian carcinoma. Recommendations for the definitive management of early stage ovarian cancer awaits completion of current GOG and European randomized prospective studies. Paclitaxel given in combination with platinum-containing agents is an intense area of research for treatment of advanced stage disease. Early data from a prospective randomized trial of patients with advanced ovarian cancer showed a higher response rate and longer disease-free survival in patients treated with paclitaxel and cisplatin compared to a standard regimen of cyclophosphamide and cisplatin. The impact of this treatment on long-term survival awaits maturation of data. Preliminary results evaluating G-CSF in combination with paclitaxel and cisplatin for dose escalation was reported. Paclitaxel, 250 mg/m2, and cisplatin, 75 mg/m2, were the maximally tolerated doses, with peripheral neuropathy or myalgias the dose limiting toxicities. Further studies are now underway to test the effect of dose-response with escalation therapies and to determine the optimal dose and schedule for the management of patients with advanced ovarian cancer. IL-3 significantly ameliorated neutropenia but did not prevent cumulative platelet toxicity in a regimen utilizing high-dose carboplatin. This mild improvement in myelosuppression was obtained at the cost of significant toxicity. Nausea, vomiting, malaise, bone pain, headache, fever, chills and facial flushing were frequent. Intraperitoneal chemotherapy was tested as a means of consolidation treatment for patients after having a negative second-look laparotomy. These treatments were shown to be feasible; however, prospective randomized trials will be necessary to determine a benefit over operative therapy alone. Several studies addressed to problem of residual disease after primary surgery and adjuvant chemotherapy. A large phase II study conducted by the GOG confirmed the activity of salvage cisplatin-based intraperitoneal chemotherapy in patients with small-volume residual ovarian cancer with favorable pretreatment characteristics. Whether intraperitoneal platinum-based therapy represents an advantage over systemic platinum therapy is being addressed in a prospective SWOG study. The use of six additional cycles of CAP for treatment of residual disease after primary treatment of surgery and adjuvant chemotherapy did not significantly improve complete pathological response and survival. Prolonged duration of chemotherapy above six cycles is not likely to impact treatment for residual disease. A regimen of high dose carboplatin was compared to whole abdominal radiotherapy for treatment of residual disease after initial chemotherapy. There was no difference in survival or disease-free survival between treatments.(ABSTRACT TRUNCATED)