RESUMO
Brain metastases are common in advanced melanoma and cause death in >50% of patients. Until recently, median survival was only â¼4 months. Improved systemic treatment including immune checkpoint inhibitors and combinations of BRAF/MEK inhibitors, however, has significantly improved intracranial tumor response and survival. In addition, advances in radiation therapy have also improved the intracranial outcomes for advanced melanoma patients with brain metastases (MBM). There has long been concern that systemic treatment of the central nervous metastases would be ineffective due to inability of active agents to cross an intact blood-brain barrier. Recent studies have shown, however, that highly active systemic therapy can have significant benefit in these patients. When determining a patient's treatment, the important factors in predicting the likelihood of benefit including the presence of neurologic symptoms, the number and size of brain metastases, performance status/status of extracranial disease, and BRAF mutation status should all be considered. In this review, we will discuss the challenges and treatment options for patients with advanced melanoma and brain metastases.
Assuntos
Neoplasias Encefálicas , Melanoma , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Melanoma/terapia , Melanoma/genética , Neoplasias Encefálicas/diagnóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
AIM: We describe the feasibility of combining infusional 5-fluorouracil (5-FU) with intraoperative radiation therapy (IORT). METHODS: Patients with surgically resectable locally advanced gastrointestinal cancers were treated concurrently during surgery with IORT and a 72 h infusion of 5-FU. Patients without previous external beam radiation therapy (EBRT) were subsequently treated with EBRT (40-50Gy) concurrent with a 21-day continuous infusion of 5-FU. Pancreatic, gastric, duodenal, ampullary, recurrent colorectal, and recurrent anal cancer were included. RESULTS: During IORT/5-FU, no chemotherapy-related grade III or IV hematologic or gastrointestinal toxicity was noted. Post-surgical recovery or wound healing was not affected. One of nine patients who received post-operative radiation required a treatment break. During follow-up, there were more complications in patients with pelvic tumours, especially those with previous radiation. Nine patients have had local and/or local regional recurrences, two of these in the IORT field. CONCLUSIONS: Treatment with a combination of IORT and 5-FU followed by EBRT and 5-FU is feasible. However, long-term complications may be increased in previously irradiated recurrent pelvic tumours.
Assuntos
Adenocarcinoma/terapia , Antineoplásicos/administração & dosagem , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Fluoruracila/administração & dosagem , Neoplasias Gastrointestinais/terapia , Radioterapia/métodos , Adulto , Idoso , Terapia Combinada , Estudos de Viabilidade , Feminino , Humanos , Infusões Intravenosas , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Radioterapia de Alta Energia , Resultado do TratamentoRESUMO
We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with >or= 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150-775 mg/m(2)infused over 24 hours, doxorubicin 165 mg/m(2)as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg(-1). There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m(2) dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan-Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51-83%) and 77% (95% CI; 64-93%). Paclitaxel up to 725 mg/m(2) infused over 24 hours in combination with with doxorubicin 165 mg/m(2) and cyclophosphamide 100 mg kg(-1) is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Paclitaxel/efeitos adversos , Adulto , Área Sob a Curva , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/farmacocinética , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Resultado do TratamentoRESUMO
Opportunities for the treatment of melanoma with high-dose chemotherapy have been inadequately explored because of the failure of early studies to demonstrate an advantage for high doses of those agents with disease activity that could also be safely dose-escalated without excessive extramedullary toxicities. However, emerging concepts of tumor and transplantation immunology have recently coincided, providing the rationale for new strategies that exploit principles of allogeneic transplant to overcome immunologic tolerance and escape mechanisms in the tumor-bearing individual. It is hoped that this setting will provide an improved milieu for donor-derived immunotherapeutic intervention that takes advantage of shared tumor antigens with therapeutic potential shown in a variety of tumor vaccination studies.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunoterapia , Melanoma/terapia , Antígenos de Neoplasias/imunologia , Humanos , Melanoma/imunologia , Transplante Autólogo , Transplante HomólogoRESUMO
PURPOSE: In recognition of the variety of available chemotherapeutic modulating agents and their potential to enhance the efficacy of platinum-based therapy, we embarked upon a phase I study to investigate the feasibility of combining fixed doses of carboplatinum (CBDCA) and etoposide (VP-16) with 24-h concurrent infusions of dipyridamole (DP), prochlorperazine (PCZ) and cyclosporine A (CSA) administered in escalating doses. METHODS: Patients received intravenous VP-16 (200 mg/m2) and CBDCA (300 mg/m2), each over 30 min, starting at hour 6 of the modulator infusions. Resistance modulators were escalated sequentially to determine their respective maximally tolerated doses (MTDs). The pharmacokinetics (PK) of VP-16, CBDCA, and the three drug resistance (DR) modifiers were studied in eight patients. RESULTS: A total of 59 patients were entered on study. The MTD was established at DP 5 mg/kg per day, PCZ 24 mg/h, and CSA 9.5 mg/kg per day. Dose-limiting toxicities included hypotension and severe sedation, presumably related to PCZ. No objective responses were seen. PK studies were performed when PCZ and DP doses were 24 mg/h and 3.3 mg/kg, and the CSA dose was either 8.5 mg/kg (five patients) or 9.5 mg/kg (three patients). The median clearance of VP-16 was 0.96 l/h per m2 (range 0.8-1.5 l/h per m2), which is lower than for VP-16 alone and similar to previously reported effects of CSA on VP-16 elimination. The median measured CBDCA AUC was 3.0 mg/ml x min (range 2.4-4.8 mg/ml x min). CBDCA AUC predicted by the Calvert formula using measured creatinine clearance underestimated the actual AUC in seven of the eight patients, in one case by as much as twofold. The median end of infusion PCZ and total DP plasma concentrations were 1.2 microM (range 0.5-2.2 microM) and 4.4 microM (range 1.3-5.9 microM), respectively, consistent with in vitro resistance modulatory levels. However, free DP was only 0.02 microM (range 0.004-0.04 microM). The median CSA level at 24 h of 1450 microg/l (range 1075-1640 microg/l) is in agreement with concentrations required for partial DR reversal in vitro, although it is much lower than levels achieved in our previous phase I study of CBDCA + CSA alone using similar doses of CSA. The CSA dose on the current trial was escalated beyond the MTD for the previous phase I study, suggesting that there may be an interaction between CSA and one of the other modulators. CONCLUSION: These results demonstrate that in vitro DR-reversing levels of two of the three agents used in this study can be achieved in vivo, and that this combination of DR modulators has significant effects on the pharmacokinetics of VP-16.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antieméticos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/administração & dosagem , Ciclosporina/administração & dosagem , Dipiridamol/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Proclorperazina/administração & dosagem , Resultado do Tratamento , Vasodilatadores/administração & dosagemRESUMO
Cytogenetic abnormalities are used to define prognostic subgroups of acute myelogenous leukemia (AML) with respect to achieving complete remission (CR) and remaining disease free. These prognostic groups for obtaining CR were based on an induction regimen mainly using standard dose cytosine arabinoside (Ara-C) + daunorubicin (DNR). We have reviewed our experience with 122 adult patients with de novo non-M3 AML who were treated with high-dose (HD) Ara-C 3 g/m2 given over 3 h every 12 h for a total of eight doses followed by DNR 60 mg/m2 daily for 2 days. CR was obtained in 80% while 16% had refractory disease and 4% died of sepsis during hypoplasia. CR rate for favorable, intermediate and unfavorable cytogenetic groups were 87%, 79% and 62%, respectively (P = 0.32). High white blood cell count, age, FAB subtype and LDH levels did not adversely affect CR rate. Eighty-five percent of patients achieved CR with one course of treatment and 87% of complete responders were able to receive post remission therapy. High-dose Ara-C/DNR appears to offer an excellent chance of achieving remission for patients with AML including those with poor risk cytogenetics, without an increase in early toxic deaths.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Leucemia Mieloide/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cerebelares/induzido quimicamente , Deleção Cromossômica , Inversão Cromossômica , Cromossomos Humanos/genética , Cromossomos Humanos/ultraestrutura , Cromossomos Humanos Par 7 , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Feminino , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Sepse/etiologia , Translocação Genética , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. METHODS: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200-1500 mg/m2, followed by a 23-h infusion of 800-6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. RESULTS: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 microM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 +/- 41 ml/min per m2) versus without CNS disease (59 +/- 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. CONCLUSION: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (> 1 microM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.
Assuntos
Neoplasias Meníngeas/tratamento farmacológico , Metotrexato/farmacocinética , Adulto , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Leucovorina/uso terapêutico , Neoplasias Pulmonares/patologia , Masculino , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/secundário , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/líquido cefalorraquidiano , Metástase Neoplásica , Osteossarcoma/patologiaRESUMO
Interleukin-2 (IL-2) administered in pharmacologic doses to renal cancer patients with intact organ function and good performance status induces durable complete responses in about 5% of patients and partial responses in an additional 10% to 15%. The mechanism of antitumor efficacy of IL-2 is closely related to its ability to expand and activate cytotoxic lymphocytes of the natural killer (NK)- and thymic (T)-cell subsets that express IL-2 receptors (IL-2R). There is also accumulating evidence that local or generalized effector cell dysfunction, which is characteristic of patients with advanced cancer, can be reversed with IL-2 exposure. The toxicities of IL-2 are mediated by cytokines and other small molecules secreted by IL-2R-expressing cells responding to the binding of this ligand. The common mechanism for IL-2-induced multiorgan dysfunction appears to be a capillary leak syndrome directly mediated by local production of nitric oxide by cells of the monocyte-macrophage lineage. To date, efforts to improve on the antitumor activity of IL-2 by the addition of IL-2-activated peripheral blood mononuclear cells (lymphokine-activated killer [LAK] cells) or cell subsets selected for proximity or potential antigen-specificity (tumor-infiltrating lymphocytes [TIL]) have not led to improved therapeutic outcomes. Attempts to reduce the risks of IL-2 therapy (which could potentially allow for increased IL-2 administration) by blocking one or more of the known mediators of toxicity have also been disappointing. Current research is directed at developing combination regimens with additive or synergistic antitumor effects and incompletely overlapping toxicities, as well as the identification of tumor antigens that may be the target of more focused cellular therapies. The role of high-dose IL-2 in the adjuvant therapy of resected renal cancer at high risk of relapse is also under investigation.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/terapia , Interleucina-2/uso terapêutico , Neoplasias Renais/terapia , Carcinoma de Células Renais/imunologia , Ensaios Clínicos Fase I como Assunto , Terapia Combinada , Esquema de Medicação , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Neoplasias Renais/imunologia , Células Matadoras Ativadas por Linfocina/efeitos dos fármacos , Células Matadoras Ativadas por Linfocina/transplante , Nefrectomia , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida , Tireoidite Autoimune/induzido quimicamenteRESUMO
The therapeutic benefit of adding interferon alpha (IFNalpha) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNalpha, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNalpha plus dacarbazine over dacarbazine alone, we treated patients with an "induction" regimen of IFNalpha, 15 mU m(-2) day(-1) intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNalpha, 5 mU m(-2) day(-1) subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m(-2) day(-1) and cisplatin 33 mg m(-2) day(-1) for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNalpha and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%-20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/secundário , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Dacarbazina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sudoeste dos Estados Unidos , Tamoxifeno/administração & dosagem , Resultado do TratamentoRESUMO
In this pilot trial of interleukin (IL)-2-treated autologous bone marrow (BM) and peripheral stem cell (PSC)-supported high-dose chemoradiotherapy, we report 36 patients with poor-prognosis leukemia and lymphoma who received BM and/or granulocyte colony-stimulating factor (G-CSF)-mobilized autologous PSCs that had been exposed to IL-2 for 24 hours ex vivo. Patients then received IL-2 by low-dose continuous intravenous (i.v.) infusion until hematologic reconstitution and then by intermediate-dose continuous i.v. infusion for six 2-week maintenance cycles given at 1-month intervals. The median Day to neutrophils over 500/microL was 22 with BM and 10 with PSCs (p = 0.01). The median Day to platelets >20,000/microL was 50 for BM and 25 for PSCs, and to platelets >50,000/microL was 138 for BM and 34 for PSCs (p not significant). After the first three patients received IL-2 at 2 mIU x m(-2) x day(-1) and had slow reconstitution, four patients were treated without IL-2 until the maintenance phase following reconstitution. The remaining 29 patients received the initial "post-infusion" IL-2 at 1 mIU x m(-2) x day(-1). Toxicities associated with the infusion of IL-2-activated cells consisted of chills and fever in about one-half of the patients and transient hypotension in 12%. Low-dose IL-2 by continuous i.v. infusion in the early posttransplant period was associated with exacerbation of fever, diarrhea, and altered mental status in a minority of patients. The major dose-limiting toxicities of maintenance IL-2 were fever, fatigue, gastrointestinal symptoms, skin rash, and dyspnea. Among 24 lymphoma patients, nine are in continuous complete remission (CCR) from 18-48 months, and 15 have died (12 due to relapse and three of therapy-related toxicities). Of 12 acute leukemia patients, two with acute lymphoblastic leukemia (ALL) are in CCR at 38 and 43 months, and one patient who was in cytogenetic but not molecular remission of Philadelphia chromosome-positive ALL died of progressive leukemia at Day 108. Three of nine with myeloid leukemia are in CCR at 21, 46, and 53 months; one is in hematologic and cytogenetic remission of acute promyelocytic leukemia at 55 months with multiple new cytogenetic abnormalities; one is alive at 54 months with pancytopenia after incomplete hematologic recovery followed by multiple new cytogenetic abnormalities (myelodysplasia); and one had an unrelated donor transplant after relapsing 4 months following protocol therapy. One myeloid leukemia patient remains without evidence of relapse, but is transfusion-dependent at 15 months following transplant.
Assuntos
Transplante de Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Interleucina-2/uso terapêutico , Leucemia/terapia , Linfoma/terapia , Doença Aguda , Adolescente , Adulto , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Transplante Autólogo , Resultado do TratamentoRESUMO
PURPOSE: The Intergroup conducted this breast cancer adjuvant trial to compare an investigational 16-week regimen with cyclophosphamide, doxorubicin, and fluorouracil (5-FU; CAF). The 16-week regimen features greater doxorubicin and 5-FU dose-intensity than CAF and improved scheduling of antimetabolites with sequential methotrexate and 5-FU, as well as infusion 5-FU. PATIENTS AND METHODS: A total of 646 node-positive, receptor-negative patients were randomly assigned to receive either the 1 6-week regimen or six cycles of CAF. Breast cancer outcomes included recurrence as well as disease-free and overall survival. Toxicity was evaluated by the Common Toxicity Criteria (CTC). Treatment-related quality of life was assessed by the Breast Chemotherapy Questionnaire (BCQ) before, during, and 4 months after treatment in 163 patients. The trial was designed to use one-sided tests of significance for power calculations, but is now reported with both one-sided and the traditional two-sided tests of significance. RESULTS: At a median follow-up of 3.9 years, the estimated 4-year recurrence-free survival rate was 67.5% with the 16-week regimen versus 62.7% with CAF (P = .19, two-sided; P = .095, one-sided). The estimated 4-year survival rate was 78.1% with the 16-week regimen versus 71.4% with CAF (P = .10, two-sided; P = .05, one-sided). CAF produced significantly higher grades of leukopenia, granulocytopenia, and thrombocytopenia, as well as liver and cardiac toxicity, whereas the 16-week regimen produced significantly higher grades of anemia, nausea, stomatitis, and weight loss, as well as skin and neurotoxicity. There were three treatment-related deaths with CAF but none with the 16-week regimen. During treatment, quality of life declined significantly more with the 16-week regimen than CAF, but by 4 months posttreatment, there was no difference. CONCLUSION: The 16-week regimen produced marginally better breast cancer outcomes than CAF with similar toxicity but a greater reduction in during-treatment quality of life. The 16-week regimen should not be used instead of a standard-dose regimen without careful consideration of the 16-week regimen's pros and cons, which include its complicated schedule. It should probably not be tested further, but its antimetabolite schedules and frequent drug administration (ie, dose density) should be considered in the development of new regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Metástase Linfática , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: The combination of carmustine (BCNU), dacarbazine (DTIC), cisplatin (DDP), and tamoxifen (Tam) has been reported in small series to provide a response rate of 50%, but with significant myelosuppression and risk of thromboembolic complications. We performed this phase II study to assess the antitumor activity and important toxicities of this combination in the cooperative group setting. PATIENTS AND METHODS: Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment. Treatment cycles were repeated every 6 weeks in responding or stable patients for a maximum duration of 1 year. RESULTS: Twelve objective responses were achieved (response rate 15%, 95% confidence interval 8%-25%). Five responses were complete (CR) and seven were partial (PR). The median response duration was 8+ (range, 4-19+) months, (16+ [4-19+] for CR and 8+ [4-11] for PR), and the median survival of the entire group was 9 months. The toxicities were predominantly neutropenia and thrombocytopenia. Four patients developed thromboembolic events. Two patients died while on protocol therapy, one with complications of neutropenia, and the other with disease progression. CONCLUSION: The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity. We do not recommend this combination for routine treatment of advanced melanoma or as the control arm in randomized studies of combination therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Feminino , Humanos , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Tamoxifeno/efeitos adversos , Tamoxifeno/análiseRESUMO
The success of allogeneic transplantation is in part due to the immunotherapeutic effect mediated by the graft. Autologous transplantation is hampered by the absence of this effect, leading to a higher relapse rate. We have conducted a series of studies designed to augment the immunologic activity of the graft after autologous transplant with a view towards introducing an autologous graft-versus-tumor effect that could decrease the rate of relapse after autologous transplant. These studies have included IL-2 activation of marrow followed by post-transplant infusional IL-2, the development of a novel protocol for the generation of highly efficient cytotoxic effector cells, termed cytokine-induced killer (CIK) cells, with broad and potent antitumor activity. In order to determine the potential for generating peptide-specific cytolytic T cells, studies have been conducted upon transducing antigen-presenting cells (APC) with AAV vector-mediated gene transfer, a vector capable of transducing non-proliferating target cells. Transduction of human monocytes and macrophages resulted in high expression of the transduced gene. This latter study forms the basis for determining whether genetic modification of APC can potentiate specific immune responses to tumor-specific gene products. Taken together, these strategies will hopefully increase the therapeutic efficacy of autologous transplantation.
Assuntos
Transplante de Medula Óssea/métodos , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Imunoterapia Adotiva/métodos , Animais , Humanos , Transplante AutólogoRESUMO
The major cause of treatment failure in hematologic malignancies is the development of resistance to chemotherapeutic agents and the presence of clonogenic tumor cells in remission bone marrow. In the present study, we tested the optimal conditions for activation by interleukin-2 (IL-2) of endogenous bone marrow effector cells to develop cytotoxicity against solid tumor and leukemia cells and the effects of IL-2 treatment on eradication of malignant cells from the marrow product while preserving hematopoiesis. Normal donor bone marrow was contaminated with 10% A549 lung cancer cells, MCF-7 breast cancer, or EM2 leukemia cells, and then combined with peripheral blood-derived lymphokine-activated killer (LAK) cells which had been incubated in the presence of IL-2, 6000 IU/ml, for 5 days. Eradication (A549 and MCF-7) or >90% reduction in tumor cell number (EM2) was achieved upon exposure of the marrow to LAK cells but not to control, non-IL-2-exposed PBMC. The non-cross-resistance of chemotherapy and cell-mediated cytotoxicity were tested by using chemoresistant target cells for LAK cytotoxicity assays. Ara-C-resistant K562 cells were sensitive to LAK cytotoxicity, similar to sensitive controls. Similar effects were seen in daunomycin-resistant HL60 leukemia cells and VP-16-resistant K562 cells. The daunomycin-resistant K562 cells were also sensitive to LAK cell killing similar to sensitive controls. Activation of bone marrow mononuclear cells (BMMC) with IL-2, 6000 IU/ml for 24 h, significantly enhanced cytotoxicity against the NK-resistant, LAK-sensitive Daudi cell line. This procedure did not result in significant loss of total BMMC or hematopoietic colony-forming units. We then studied the possibility that the effector cell activity of the IL-2-activated BMMC which is diminished after removal of the IL-2 at 24 h could be recovered upon re-exposure of the marrow to IL-2. We found that the optimum conditions for preserving cytotoxicity were prolonged continuous exposures to IL-2 but that re-exposure of the 24-h IL-2-activated BMMC to IL-2 after a 1- or 2-week IL-2 withdrawal was associated with full recovery of cytotoxicity. These experiments also demonstrated that the overall recovery of viable cells from the BMMC was over 100%, possibly due to a proliferative effect of the IL-2 exposure on BMMC. These results demonstrate that the use of IL-2-activated marrow in patients with acute leukemia in remission undergoing autologous bone marrow transplantation (aBMT) may overcome the obstacles of clonogenic, drug-resistant minimal residual disease. The effector cell activity and hematopoietic capacity of the activated bone marrow product can also be maintained even if optimal clinical care requires an interruption in the in vivo exposure to IL-2. This therapeutic approach is currently being tested in acute leukemia patients undergoing IL-2-activated aBMT followed by prolonged IL-2 treatment before and after hematologic reconstitution.
Assuntos
Purging da Medula Óssea , Transplante de Medula Óssea , Células-Tronco Hematopoéticas/fisiologia , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Neoplasias da Mama/patologia , Ensaio de Unidades Formadoras de Colônias , Citarabina/toxicidade , Citotoxicidade Imunológica/efeitos dos fármacos , Daunorrubicina/toxicidade , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/toxicidade , Feminino , Células HL-60/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Humanos , Células Matadoras Ativadas por Linfocina/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Leucemia/patologia , Leucemia/terapia , Neoplasias Pulmonares/patologia , Doadores de Tecidos , Transplante Autólogo , Transplante Homólogo , Células Tumorais CultivadasRESUMO
Interleukin 6 (IL-6) has antitumor activity comparable to IL-2 in murine models with less toxicity. Because the biological effects of intermittent and continuous infusions may differ, we conducted two concurrent Phase I trials of daily x5, 1-h, and continuous 120-h i.v. infusions to determine the toxicity, biological effects, and maximum tolerated dose of i.v. IL-6. Cohorts of six patients with advanced cancer received escalating doses (1, 3, 10, 30, 100, and 150 microgram/kg/day) of recombinant human IL-6 on days 1-5 and 8-12 of each 28-day course (1-h trial) or on days 1-5 of each 21-day course (120-h trial). Treatment was administered in regular inpatient wards and in outpatient clinics and was withheld in the event of grade 3 toxicity. Sixty-nine patients (1-h trial, n = 40; 120-h trial, n = 29) were enrolled, including 27 with renal cancer and 16 with melanoma. All were ambulatory, and 40 were asymptomatic. Fever (97%), anemia (78%), fatigue (56%), nausea or vomiting (49%), and elevated serum transaminase levels (42%) were the most frequent toxicities. Transient hypotension developed in 23 patients (33%). There were three deaths during the study due to progressive disease and/or infection. There were no objective responses. Dose-related increases in platelet counts and C-reactive protein levels were detected in most patients. Principal dose-limiting toxicities included atrial fibrillation (1 episode in the 1-h trial and 4 episodes in the 120-h trial) and neurological toxicities (3 episodes in the 1-h trial and 4 episodes in the 120-h trial). The neurological toxicities included confusion, slurred speech, blurred vision, proximal leg weakness, paraparesis, and ataxia. These effects were transient and reversed when IL-6 was discontinued. IL-6 can be given by i.v. infusion at biologically active doses with acceptable toxicity. Dose-limiting toxicities consisted mainly of a spectrum of severe but transient neurological toxicities and occasional episodes of atrial fibrillation. The maximum tolerated doses recommended for use with these i.v. schedules in Phase II trials are 100 microgram/kg/day by daily x5 1-h infusion and 30 microgram/kg/day by 120-h infusion. Phase II trials will be performed to determine the antitumor activity of IL-6 and better define its toxicity. Patients in these and other IL-6 studies should be monitored closely for neurological and cardiac effects.
Assuntos
Antineoplásicos/uso terapêutico , Interleucina-6/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Interleucina-6/administração & dosagem , Interleucina-6/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Resultado do TratamentoRESUMO
A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/ m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R2 = 0.71, n = 18, P < 0.0001). The mean +/- SE concentrations were 93 +/- 16, 230 +/- 6 and 302 +/- 27 microM at 1, 2 and 3.2 g/m2 per day, respectively. The mean +/- SE renal and nonrenal clearances of hydroxyurea were 2.14 +/- 0.18 and 3.39 +/- 0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean +/- SE half-life of 3.25 +/- 0.18 h (n = 17). The steady-state concentration of hydroxyurea was > 200 microM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents.
Assuntos
Antineoplásicos/farmacocinética , Hidroxiureia/farmacocinética , Neoplasias/metabolismo , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Infusões Intravenosas , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamenteRESUMO
PURPOSE: To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS: Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS: Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION: This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Purging da Medula Óssea , Transplante de Medula Óssea , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/terapia , Irradiação Corporal Total , Adolescente , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Purging da Medula Óssea/métodos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/uso terapêutico , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/radioterapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Análise de Regressão , Indução de Remissão , Transplante AutólogoRESUMO
Recombinant human interleukin 3 (rhIL-3, expressed in Escherichia coli) is a hematopoietic growth factor with protean biological effects on bone marrow in animal models, including enhanced granulocyte and platelet production and the capacity to ameliorate chemotherapy-induced bone marrow toxicity. We, therefore, undertook a Phase I trial in patients with advanced solid tumors and normal bone marrow function. Cohorts of four to six patients each received daily s.c. doses of rhIL-3 (SDZ-ILE-964; Sandoz) at dose levels of 1. 0, 2.5, 5.0, and 10.0 microgram/kg according to the following schedule: cycle 1, rhIL-3 days 1-14; cycle 2, carboplatin (350 mg/m2) on day 1 and etoposide (100 mg/m2) on days 1-3; and cycle 3, carboplatin (350 mg/m2) on day 1, etoposide (100 mg/m2) on days 1-3, and rhIL-3 on days 4-17. Each cycle was a total of 28 days. An analysis of 20 patients entered into all four escalating dose levels revealed that, during cycle 1, absolute neutrophil count (ANC) increased from a median baseline of 6,643/mm3 to a median of 12,692/mm3, and platelets increased from a median baseline of 314,000/mm3 to a median of 465,000/mm3. When cycle 2 was compared with cycle 3, the median ANC nadir increased from 192/mm3 to 988/mm3, and the mean ANC nadir increased from 458/mm3 to 1,297/mm3. Median platelet count nadirs increased from 29,000/mm3 to 84,000/mm3, and the mean nadir platelet counts increased from 72,000/mm3 to 129,000/mm3. Total days on which platelets were <50,000/mm3 was 52 for cycle 2 and 19 for cycle 3. The maximum tolerated dose of rhIL-3 was 5.0 microgram/kg/day; dose-limiting toxicities included fatigue, chills, fever, and headache. These data suggest a clear but variable biological activity observed with IL-3, as measured by the reduction in the depth and duration of thrombocytopenia and/or neutropenia when cycle 2 was compared with cycle 3. rhIL-3 is a promising cytokine that may help to ameliorate the bone marrow toxicity observed with the use of chemotherapeutic agents.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interleucina-3/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Humanos , Interleucina-3/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neutrófilos/efeitos dos fármacos , Contagem de Plaquetas/efeitos dos fármacos , Transfusão de Plaquetas , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Trombocitopenia/induzido quimicamente , Trombocitopenia/prevenção & controleAssuntos
Carcinoma de Células Renais/terapia , Interleucina-6/administração & dosagem , Interleucina-6/uso terapêutico , Neoplasias Renais/terapia , Adulto , Idoso , Carcinoma de Células Renais/complicações , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Interleucina-6/efeitos adversos , Neoplasias Renais/complicações , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecidos Moles/secundário , Neoplasias de Tecidos Moles/terapiaRESUMO
PURPOSE: To evaluate the protective effect of low-dose dopamine given as continuous infusion in patients who undergo chemotherapy with the nephrotoxin cisplatin. PATIENTS AND METHODS: Forty-two patients who received high-dose cisplatin-containing chemotherapy entered a prospective, randomized, double-blind, placebo-controlled trial. Twenty-one patients received dopamine, and 21 received placebo. Patients were to receive either infusional dopamine 2 micrograms/kg/min over 48 hours or placebo. Cisplatin 125 mg/m2 was administered 12 hours after initiating dopamine (group D) or placebo (group P). This schedule was repeated twice, 1 week apart. Measurements of serum creatinine, urinary electrolytes and creatinine, urinary excretion of epidermal growth factor (EGF), ototoxicity, parameters of hematopoietic recovery, and duration of hospitalization were analyzed. RESULTS: We observed an increase in serum creatinine level to a peak of 1.9 mg/dL (range, 0.8 to 7.8) in the dopamine group, in comparison to 1.4 mg/dL (range, 0.9 to 3.3) in the placebo group (P = .04). Urinary magnesium excretion increased and EGF excretion decreased in both groups. Urinary sodium, chloride, and potassium excretion were increased in both groups, but more so in the placebo group. Dopamine had no measurable effect on hearing loss, duration of hospitalization, or hematopoietic recovery. CONCLUSION: The use of prophylactic dopamine increased peak serum creatinine levels relative to placebo and failed to prevent cisplatin-induced renal toxicity or ototoxicity. Determination of whether dopamine could reverse chemotherapy-induced renal damage would require a randomized prospective trial.