RESUMO
No effective salvage regimen has been defined for patients with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who do not respond to first-line chemotherapy that contains anthracycline. Combined dexamethasone, cytosine arabinoside, and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have shown good response rates in HIV-negative patients with relapsed lymphomas. We retrospectively analyzed patients with refractory or relapsed AIDS-NHL who had been treated with either DHAP or ESHAP to evaluate the feasibility and efficacy of these regimens. Twenty-six patients with refractory or relapsed AIDS-NHL were treated between 1990 and 1999 either with DHAP ( n = 13) or with ESHAP ( n = 13). Only 1 patient from each group (8%) had achieved complete remission with any previous therapy, and most had progressive disease after the regimen immediately preceding DHAP or ESHAP. In the ESHAP group, 4 patients (31%) achieved complete remission (CR) and 3 patients (23%) attained partial remission (PR) for an overall response rate of 54%. The median survival was 7.1 months (range, 1-58.9+ months) from the time ESHAP was begun. Among the 3 patients with primary refractory lymphoma, there was 1 CR, 1 PR, and one patient with stable disease. In contrast, only 1 PR (7%) was observed with DHAP; the median survival was 3 months. Myelosuppression was the most significant toxicity with grade 4 neutropenia occurring in all who received ESHAP and in 54% of patients treated with DHAP. Neutropenic fever occurred in 8 (62%) ESHAP-treated and 6 (46%) DHAP-treated patients. Although hematologic toxicity is profound, ESHAP appears to be an active salvage regimen for patients with relapsed or refractory AIDS-NHL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/uso terapêutico , Cisplatino/uso terapêutico , Citarabina/uso terapêutico , Dexametasona/uso terapêutico , Etoposídeo/uso terapêutico , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Metilprednisolona/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Citarabina/administração & dosagem , Dexametasona/administração & dosagem , Quimioterapia Combinada , Etoposídeo/administração & dosagem , Humanos , Linfoma Relacionado a AIDS/prevenção & controle , Linfoma não Hodgkin/prevenção & controle , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação , Resultado do TratamentoRESUMO
Bone marrow involvement is reported in approximately 25% of patients with newly diagnosed acquired immunodeficiency syndrome-related lymphoma (ARL). Studied were 291 patients with ARL, diagnosed and treated at one medical center between 1984 and 1998. Clinical, immunologic, and pathologic characteristics of patients with bone marrow involvement were compared with those of patients without marrow involvement. Bone marrow involvement was present in 55 patients (19%). Small noncleaved lymphoma was diagnosed in 38% of the entire group and was the most common pathologic subtype in patients with bone marrow involvement (55% versus 34%; P =.008). Analysis of complete blood counts revealed a median hemoglobin level of 10.6 g/dL in both marrow-positive and marrow-negative groups. In contrast, a platelet count lower than 100 000/microL was more common in patients with bone marrow involvement (27% versus 11%; P =.02). Patients with marrow involvement were more likely to have leptomeningeal (cerebrospinal fluid [CSF]) lymphoma than patients whose marrows were uninvolved (24% versus 7%; P <.001) and were also more likely to have high lactate dehydrogenase (LDH) (P =.002), bone involvement (P <.001), and/or systemic B symptoms including fever, night sweats, and/or weight loss (P =.05). Median survival did not differ between marrow-positive and marrow-negative groups. On multivariate analysis, factors associated with decreased survival of marrow-positive patients included greater than 50% involvement (P =.002), systemic B symptoms (P =.008), and high-grade histologic type (P =.035). Marrow involvement in ARL correlates with small noncleaved pathology, thrombocytopenia lower than 100 000 mm(3), high LDH, and lymphomatous involvement of the CSF. Survival is statistically shorter in patients with greater than 50% marrow involvement, high-grade pathology, and/or systemic B symptoms.
Assuntos
Antígenos CD/análise , Medula Óssea/imunologia , Linfoma Relacionado a AIDS/fisiopatologia , Adulto , Idoso , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Bleomicina/administração & dosagem , Medula Óssea/patologia , Distribuição de Qui-Quadrado , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Imuno-Histoquímica , Leucovorina/administração & dosagem , Linfoma Relacionado a AIDS/imunologia , Linfoma Relacionado a AIDS/mortalidade , Linfoma Relacionado a AIDS/patologia , Linfoma Relacionado a AIDS/terapia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
Kaposi's sarcoma (KS) is the most common tumor associated with HIV-1 infection. Here, we report the expression, regulation, and biological effect of interleukin (IL)-8 in KS. AIDS-KS cell lines expressed higher levels of IL-8 than either human umbilical vein endothelial cells (HUVECs), human aortic smooth muscle (AoSM) cells or fibroblast cells (T1). The inflammatory cytokine IL-1beta up-regulated IL-8 expression in a time- and concentration-dependent manner in KS cell lines. IL-8 antisense oligonucleotides specifically reduced IL-8 mRNA and protein levels and inhibited KS cell growth in a dose-dependent manner. In addition, supernatant from a KS cell line induced the growth of HUVECs and angiogenesis in chicken chorioallantoic membrane assays, both of which were inhibited by IL-8 neutralizing antibody. Serum levels of IL-8 were also elevated in KS cases compared with matched controls. Modulation of IL-8 may thus be of therapeutic value in this disease.
Assuntos
Substâncias de Crescimento/genética , Interleucina-8/genética , Sarcoma de Kaposi/genética , Animais , Anticorpos Monoclonais/farmacologia , Biomarcadores Tumorais/análise , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Meios de Cultivo Condicionados/farmacologia , DNA Antissenso/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Substâncias de Crescimento/metabolismo , Humanos , Imuno-Histoquímica , Interleucina-1/farmacologia , Interleucina-8/imunologia , Interleucina-8/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos , Oligonucleotídeos/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/efeitos dos fármacos , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores de Interleucina-8A/análise , Receptores de Interleucina-8A/genética , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma de Kaposi/metabolismo , Sarcoma de Kaposi/prevenção & controle , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To assess the efficacy and toxicity of liposomal daunorubicin administered as a two-hour intravenous infusion to patients with relapsed or refractory non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Eligible patients had relapsed or refractory NHL with measurable or evaluable disease, and low grade, select intermediate grade, or mantle cell pathologic types. Prior exposure to an anthracycline or anthracenedione was allowed. Liposomal daunorubicin at a dose of 100 mg/m2 was given intravenously over a minimum of 120 minutes every 3 weeks. as a single agent. RESULTS: Thirty-three patients were accrued: twenty-three (70%) had low-grade histologies; six (18%) had intermediate-grade histologies (follicular large-cell and diffuse small cleaved); and four (12%) patients had mantle-cell lymphoma. Eighteen (55%) had received two or more prior regimens; fourteen (42%) received a prior anthracycline. A median of six cycles of liposomal daunorubicin were administered (range 1-15). Of 31 patients evaluable for response, 2 complete and 10 partial remissions were documented for a major response rate of 39% (95% confidence interval (CI): 22%-58%). The median duration of response was 19.5 months (range 4.3-41.1+). Six responders (50%) had received a prior anthracycline; one responder had mantle-cell histology. The major toxicities were grade 3 or 4 neutropenia in 26 patients (79%), mild to moderate nausea in 22 (67%), and fatigue in 16 (48%). CONCLUSIONS: Liposomal daunorubicin at 100 mg/m2 every three weeks has activity in patients with relapsed or refractory NHL, including patients with prior exposure to an anthracycline. Further studies of liposomal daunorubicin in combination with other agents are warranted.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Daunorrubicina/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Daunorrubicina/efeitos adversos , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Infusões Intravenosas , Lipossomos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/induzido quimicamenteRESUMO
Over time, the epidemiologic and demographic characteristics of AIDS have changed in the United States, while the use of highly active antiretroviral therapy has changed the natural history of the disease. The goal of the study was to ascertain any changes in the epidemiologic, immunologic, pathologic, or clinical characteristics of AIDS-related lymphoma (ARL) over the course of the AIDS epidemic. Records of 369 patients with ARL diagnosed or treated at a single institution from 1982 through 1998 were reviewed. Single institutional data were compared to population-based data from the County of Los Angeles. Significant changes in the demographic profile of patients with newly diagnosed ARL have occurred, with the later time intervals associated with a higher prevalence in women (P =.25), in Latino/Hispanic individuals (P <.0001), and in those who acquired human immunodeficiency virus (HIV) heterosexually (P =.01). These changes were similar in both countywide, population-based analyses and in those from the single institution. The median CD4(+) lymphocyte count at lymphoma diagnosis has decreased significantly over the years, from 177/dL in the earliest time period (1982-1986), to 53/dL in the last time period from 1995 to 1998 (P =.0006). The pathologic spectrum of disease has also changed, with a decrease in the prevalence of small noncleaved lymphoma (P =.0005) and an increase in diffuse large cell lymphoma (P <.0001). Despite changes in the use of antiretroviral or chemotherapy regimens, the median survival has not significantly changed.
Assuntos
Linfoma Relacionado a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/patologia , Comorbidade , Etnicidade , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Tábuas de Vida , Los Angeles/epidemiologia , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Relacionado a AIDS/imunologia , Linfoma Relacionado a AIDS/mortalidade , Linfoma Relacionado a AIDS/patologia , Masculino , Mortalidade/tendências , Estudos Retrospectivos , Fatores de Risco , Sarcoma de Kaposi/epidemiologia , Análise de SobrevidaRESUMO
PURPOSE: Although advances have been made in the treatment of AIDS-related Kaposi's sarcoma (AIDS-KS) with systemic chemotherapy, less toxic therapies are needed. IM862 is a naturally occurring peptide with antiangiogenic properties and was thus studied in patients with AIDS-KS. PATIENTS AND METHODS: IM862 was given as intranasal drops at a dose of 5 mg. Patients were randomized to two dosing schedules given in repeated cycles until disease progression or unacceptable toxicity: 5 days of therapy followed by 5 days off (n = 18) and every other day dosing (n = 26). RESULTS: Forty-two male patients and two female patients with a median age of 38 years (range, 22 to 53 years) were accrued. Twenty-one patients (47%) had more than 50 mucocutaneous lesions, 14 (32%) had lymphedema, and none had visceral involvement. Thirty-three patients (75%) had received prior systemic chemotherapy. Twenty-four patients (55%) had CD4(+) lymphocyte count = 200/mm(3). All but five patients were being treated with concurrent protease inhibitor(s), for a median of 10 months (range, 0 to 24 months). Major responses were documented in 36%, with five complete and 11 partial remissions, occurring after a median of 6 weeks (range, 3 to 26 weeks) and lasting a median of 33+ weeks (range, 12+ to 95+ weeks). Twenty-one patients had stable disease for periods of 7 to 72+ weeks. Adverse effects to IM862 were limited to mild and transient headache, fatigue, tingling, and nausea. No hematologic adverse effects attributed to treatment were reported. CONCLUSION: IM862 given as intranasal drops is well tolerated and has antitumor activity in patients with AIDS-KS. A randomized double-blinded study to define the activity of IM862 in patients with AIDS-KS is in progress.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Dipeptídeos/uso terapêutico , Fatores de Crescimento Endotelial/antagonistas & inibidores , Linfocinas/antagonistas & inibidores , Isoformas de Proteínas/antagonistas & inibidores , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Intranasal , Adulto , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Contagem de Linfócito CD4 , Dipeptídeos/administração & dosagem , Dipeptídeos/efeitos adversos , Progressão da Doença , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Inibidores da Protease de HIV/uso terapêutico , Cefaleia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Parestesia/induzido quimicamente , Indução de Remissão , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
PURPOSE: Liposomal anthracyclines are the present standard treatment for advanced AIDS-related Kaposi's sarcoma (KS). No effective therapies have been defined for use after treatment failure of these agents. A phase II trial was thus conducted with paclitaxel in patients with advanced KS to assess safety and antitumor activity. MATERIALS AND METHODS: A regimen of paclitaxel at a dose of 100 mg/m(2) was given every 2 weeks to patients with advanced AIDS-related KS. Patients were treated until complete remission, disease progression, or unacceptable toxicity occurred. RESULTS: Fifty-six patients with advanced AIDS-related KS were accrued. Tumor-associated edema was present in 70% of patients and visceral involvement in 45%. Forty patients (71%) had received prior systemic therapy; 31 of these were resistant to an anthracycline. The median entry CD4(+) lymphocyte count was 20 cells/mm(3) (range, 0 to 358). A median of 10 cycles (range, 1 to 54+) of paclitaxel was administered. Fifty-nine percent of patients showed complete (n = 1) or partial response (n = 32) to paclitaxel. The median duration of response was 10.4 months (range, 2.8 to 26.7+ months) and the median survival was 15.4 months. The main side effects of therapy were grade 3 or 4 neutropenia in 61% of patients and mild-to-moderate alopecia in 87%. CONCLUSION: Paclitaxel at 100 mg/m(2) given every 2 weeks is active and well tolerated in the treatment of advanced and previously treated AIDS-related KS. The median duration of response is among the longest observed for any regimen or single agent reported for AIDS-related KS. Paclitaxel at this dosage and schedule is a treatment option for patients with advanced AIDS-related KS, including those who have experienced treatment failure of prior systemic therapy.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos Fitogênicos/uso terapêutico , Paclitaxel/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Antineoplásicos Fitogênicos/efeitos adversos , Relação Dose-Resposta a Droga , Edema/diagnóstico , Edema/tratamento farmacológico , Feminino , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/mortalidade , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Indução de Remissão , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/mortalidade , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with cytotoxic activity against both resting and proliferating cells. Clinical studies with cladribine have reported antitumor activity against various hematologic malignancies. METHODS: The authors studied responses to cladribine among patients with low and intermediate grade non-Hodgkin's lymphoma that had been refractory to or relapsed after prior chemotherapy. Cladribine was given intravenously over 2 hours at a dose of 0.14 mg/kg daily for 5 consecutive days, repeated every 4 weeks. RESULTS: Twenty-eight patients (16 males, 12 females) with a median age of 58 years (range, 41-75 years) were accrued. Twenty-three patients had low grade and 5 had intermediate grade lymphoma. Stage IV disease was present in 22 (79%), and 17 (61%) had systemic B-symptoms. The majority (57%) had received 2 or more prior chemotherapy regimens (median, 2; range, 1-5); 6 had had prior fludarabine therapy. Major responses were documented in 32% (9 of 28 patients), with 4 complete remissions (CR) and 5 partial remissions (PR) after a median of 4 cycles (range, 1-9). One CR occurred in one patient with intermediate grade diffuse large cell lymphoma, and three of six patients who had had prior fludarabine therapy experienced CR or PR with cladribine. Severe hematologic toxicities included reversible neutropenia, protracted thrombocytopenia, and lymphopenia. Other reported adverse effects included mild-to-moderate fatigue, nausea, and diarrhea. CONCLUSIONS: Cladribine is an active single agent in the treatment of patients with refractory or relapsed advanced stage indolent lymphoma, with major responses in one third of patients.
Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Cladribina/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Taxa de SobrevidaRESUMO
PURPOSE: Kaposi's sarcoma (KS) is the most common tumor in patients with AIDS and can be fatal in patients with lung involvement. Systemic chemotherapy is the most effective treatment for pulmonary KS. We thus conducted this study to determine the efficacy of liposomal daunorubicin in the treatment of patients with pulmonary KS. METHODS: Patients with biopsy-proven, symptomatic pulmonary KS were accrued. Liposomal daunorubicin was given at a dose of 60 mg/m2 intravenously every 2 weeks. Response was monitored by chest radiographs, pulmonary function tests, arterial blood gases, and grading of pulmonary symptoms. RESULTS: Fifty-three male patients were accrued. The median CD4+ lymphocyte count was 13/microL (range, 0 to 200); 70% reported a prior AIDS-defining opportunistic infection. All patients were symptomatic, with cough reported in all patients, shortness of breath in 94%, and hemoptysis in 55%. The mean study entry diffusing capacity of carbon monoxide (DLCO) was 58.5% (percent of predicted). The median dose of liposomal daunorubicin delivered was 360 mg/m2 (range, 60 to 1,380). More than 75% of patients had complete or partial resolution of baseline pulmonary symptoms. Complete or partial improvement in DLCO was observed in 22%; complete or partial resolution of radiographic abnormalities was reported in 32%. The most common treatment-related toxicity was neutropenia, which occurred in 85%. There were no instances of cardiac toxicity observed, even at high cumulative doses. CONCLUSION: Liposomal daunorubicin at 60 mg/m2 is safe and active in patients with pulmonary KS. Trials combining liposomal daunorubicin with other active agents in KS should be considered.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antibióticos Antineoplásicos/uso terapêutico , Daunorrubicina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Antibióticos Antineoplásicos/efeitos adversos , Daunorrubicina/efeitos adversos , Esquema de Medicação , Humanos , Lipossomos , Pulmão/efeitos dos fármacos , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Sarcoma de Kaposi/etiologia , Análise de SobrevidaRESUMO
OBJECTIVE: To identify and treat a unique form of anemia in patients with long-term IDDM. RESEARCH DESIGN AND METHODS: Patients with IDDM, unexplained symptomatic anemia, and serum creatinine levels of < 177 mumol/l (2.0 mg/dl) were treated with epoetin alfa (Procrit, Ortho Biotech, Raritan, NJ), 50 U/kg three times weekly, subcutaneously, to reach a target hematocrit of 38-40%. Baseline serum erythropoietin titers were measured before drug therapy. RESULTS: Six patients were treated with epoetin alfa. Median age of the group was 74 years, with IDDM being diagnosed for a median of > 20 years. All patients had symptoms of anemia with a median hematocrit of 28.9% (range 27-31). Compared with iron deficiency control patients, the group had a limited erythropoietin (EPO) response to the degree of anemia. All patients showed increases in hematocrit, median peak of 40.9%, with median time-to-peak response of 12 weeks. Baseline symptoms of anemia resolved in all patients. No adverse effects were noted during the treatment period. CONCLUSIONS: There is a unique form of anemia in patients with long-term IDDM and clinically normal renal function who respond to low-dose epoetin alfa therapy. The rapid response to therapy and depressed baseline erythropoietin titers suggest the anemia is due to a lack of endogenous EPO release.
Assuntos
Anemia/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Eritropoetina/uso terapêutico , Hematínicos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anemia/complicações , Diabetes Mellitus Tipo 1/complicações , Relação Dose-Resposta a Droga , Epoetina alfa , Eritropoetina/administração & dosagem , Eritropoetina/sangue , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Hematínicos/administração & dosagem , Hematócrito , Humanos , Masculino , Pessoa de Meia-Idade , Potássio/metabolismo , Proteínas Recombinantes , Resultado do TratamentoRESUMO
PURPOSE/OBJECTIVES: To report on four patients with AIDS-related Kaposi's sarcoma who were treated with liposomal daunorubicin (DaunoXome, NeXstar Pharmaceuticals, Inc., San Dimas, CA) as part of phase I/II and phase III clinical trials and who experienced extravasation during IV infusion. DATA SYNTHESIS: All patients were treated with ice as an immediate intervention. In addition, two patients received treatment with multiple subcutaneous injections of steroids. Two patients experienced erythema, swelling, and pain after the extravasation. Two patients who were treated aggressively reported erythema and swelling without pain. Three patients observed changes in the texture of their skin that was accompanied by decreased sensation, which developed after 8-16 weeks. These changes completely resolved in all patients receiving intervention after six months. None of the patients suffered tissue necrosis. CONCLUSIONS: Extravasation with liposomal daunorubicin is notable for the absence of tissue necrosis that typically is observed with anthracyclines. Long-term effects were limited to skin discoloration and decreased sensation, both of which resolved in all patients. IMPLICATIONS FOR NURSING PRACTICE: The lack of observed skin necrosis with daunorubicin suggests a treatment advantage with a reduction in the required aggressive extravasation procedures for free anthracyclines as well as increased safety for the patient. Additional data is needed to confirm these observations.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antibióticos Antineoplásicos/efeitos adversos , Daunorrubicina/efeitos adversos , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Ensaios Clínicos como Assunto , Daunorrubicina/administração & dosagem , Portadores de Fármacos , Humanos , Infusões Intravenosas/efeitos adversos , Lipossomos , Masculino , Pessoa de Meia-Idade , Sarcoma de Kaposi/virologiaRESUMO
BACKGROUND: In vitro and in vivo clinical studies have shown that certain preparations of human chorionic gonadotropin have antitumor activity against Kaposi's sarcoma, the most common tumor in patients infected with human immunodeficiency virus type 1 (HIV-1). METHODS: A phase I trial was conducted in 18 male patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma. Successive cohorts of six patients each received human chorionic gonadotropin (A.P.L.; Wyeth-Ayerst, Radnor, PA) subcutaneously at doses of 5000 IU daily (level I), 10,000 IU three times a week (level II), or 10,000 IU daily (level III). Toxic effects, changes in reproductive hormone levels, HIV-1 RNA plasma levels, and response to therapy were evaluated. RESULTS: A.P.L. treatment was well tolerated at all dose levels, and no maximum-tolerated, dose-defined toxic effects were observed at the highest dose tested. The most common side effects were weight gain, increased libido, and increased energy. A persistent increase in testosterone level and a persistent decline in luteinizing hormone and follicle-stimulating hormone levels were seen over time. Major responses were observed in six patients. Partial remissions (> or =50% decrease in lesion numbers, volume, or surface area) were observed at dose level I and dose level II (two patients each); biopsy-confirmed complete remissions (resolution of all lesions) were observed at dose level III (two patients). All but one major response have persisted from 207 to more than 515 days. Nine patients had stable disease lasting 10 weeks or longer. CONCLUSIONS: A.P.L. given at daily doses ranging from 5000 to 10,000 IU has antitumor activity in patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma. A.P.L. can be given for more than 1 year with minimal side effects. Larger efficacy studies are warranted.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos/uso terapêutico , Gonadotropina Coriônica/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Antineoplásicos/administração & dosagem , Gonadotropina Coriônica/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Sarcoma de Kaposi/virologia , Neoplasias Cutâneas/virologia , Resultado do TratamentoRESUMO
PURPOSE: To define the maximum tolerated dose of doxorubicin when combined with fixed doses of bleomycin, vincristine, zidovudine, and recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) in patients with advanced AIDS-related Kaposi's sarcoma. PATIENTS AND METHODS: Twenty male patients were treated with zidovudine at doses of either 100 or 200 mg by mouth every 4 hours, and cytotoxic chemotherapy with bleomycin 10 U/m2 and vincristine 1.4 mg/m2 by vein every 2 weeks. Four successive cohorts received fixed doses of doxorubicin given intravenously every 2 weeks: two cohorts each received 10 mg/m2 (levels 1, 2) or 20 mg/m2 (levels 3, 4). The first cohort received rhGM-CSF at a dose of 10 micrograms/ kg, given subcutaneously on days 2 through 11 (level 1). Due to toxicity, the dose of rhGM-CSF was reduced to 5 micrograms/kg (levels 2, 3) and then to 2.5 micrograms/kg (level 4). RESULTS: The dose-limiting toxicity was severe neutropenia, occurring in 10 patients. Severe neutropenic episodes occurred after a median of three cycles of chemotherapy, with the nadir occurring after 14 days (median). Moderate neutropenia occurred in 14% of all cycles administered. Constitutional toxicities of moderate or greater severity occurred in four patients. Five of 10 patients at a doxorubicin dose of 20 mg/m2 (levels 3 and 4) experienced severe neutropenia. Thus, doxorubicin at 10 mg/m2, with BV (bleomycin, vincristine chemotherapy), zidovudine (100 mg five times daily), and rhGM-CSF (5 micrograms/kg/day), was defined as the maximum tolerated dose. CONCLUSIONS: The maximum tolerated dose of doxorubicin is 10 mg/ m2 every 2 weeks when given in combination with BV chemotherapy, zidovudine, and rhGM-CSF. While the addition of rhGM-CSF at doses of 2.5 to 5 micrograms/kg decreased the duration of neutropenia, it did not prevent the occurrence of severe neutropenia from combined myelotoxic therapy.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Doxorrubicina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Pulmão/efeitos dos fármacos , Masculino , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Resultado do Tratamento , Vincristina/administração & dosagem , Zidovudina/administração & dosagemRESUMO
PURPOSE: To define the safety and toxicity of interleukin-4 (IL-4) when administered subcutaneously in patients with AIDS-related Kaposi's sarcoma (AIDS-KS); to evaluate the effect of IL-4 on immunologic and virologic parameters; and to preliminarily assess the response rate of IL-4 in AIDS-KS. PATIENTS AND METHODS: Eighteen patients with mucocutaneous, non-visceral AIDS-KS were treated with IL-4 at a dose of 1 mcg/kg subcutaneously, daily until unacceptable toxicity or for a maximum period of six months. Twelve (66%) patients had extensive mucocutaneous disease with over 25 lesions. Ten patients had received prior systemic chemotherapy. Seventeen had CD4+ lymphocyte counts less than 200/mm3. RESULTS: The most common adverse effects included headache in 78%, fever in 56%, chills in 44%, and edema in 44%. Hematologic toxicities consisted of grade 4 neutropenia (less than 500/mm3) in 33%, mild anemia in 22%. Transient elevation of liver enzymes was noted in 17%. A transient elevation in CD4+ lymphocyte counts occurred during the first two weeks of therapy. Four of eleven patients tested showed marked decline in plasma HIV RNA after four weeks. Partial remission was observed in one patient, lasting six months. Three other patients (17%) had stable disease: 7 weeks in one patient, and 10 weeks in each of the two other patients. CONCLUSION: Grade 4 neutropenia (absolute neutrophil count < 500/mm3) was the most common hematologic adverse effect with IL-4 in patients with AIDS-KS. In contrast to in vitro findings, there was a decrease in plasma HIV RNA after four weeks of IL-4 therapy in the majority of patients tested. IL-4 produced minimal anti-tumor effects in AIDS-KS with one partial remission in a patient with CD4 lymphocyte counts over 200/mm3. Further studies of IL-4 in AIDS-KS may be considered in patients with better immune status.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Fatores Imunológicos/uso terapêutico , Interleucina-4/uso terapêutico , Neoplasias Bucais/terapia , Sarcoma de Kaposi/terapia , Neoplasias Cutâneas/terapia , Adulto , Contagem de Linfócito CD4/efeitos dos fármacos , Linfócitos T CD8-Positivos , Síndrome de Vazamento Capilar/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/terapia , Progressão da Doença , Febre/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Proteína do Núcleo p24 do HIV/sangue , HIV-1/isolamento & purificação , Cefaleia/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Injeções Subcutâneas , Interleucina-4/administração & dosagem , Interleucina-4/efeitos adversos , Contagem de Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/etiologia , Neoplasias Bucais/imunologia , Indução de Remissão , Sarcoma de Kaposi/etiologia , Sarcoma de Kaposi/imunologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/imunologia , Resultado do Tratamento , Viremia/etiologia , Viremia/imunologia , Viremia/terapiaRESUMO
BACKGROUND: Kaposi's sarcoma is the most common cancer in patients with the acquired immunodeficiency syndrome (AIDS). Recently, certain preparations of human chorionic gonadotropin (hCG) have been shown to inhibit the growth of Kaposi's sarcoma cell lines in vitro and in immunodeficient mice. METHODS: After in vitro evaluation of four commercially available hCG preparations, the most active product was evaluated in 36 patients with AIDS-related Kaposi's sarcoma. In a phase 1-2 trial, 24 patients received intralesional injections of hCG three times a week for two weeks at doses of 250, 500, 1000, or 2000 IU (6 patients each). In each patient three nodular lesions were injected, two with the drug and one with diluent alone. In a double-blind trial, 12 additional patients were randomly assigned to receive intralesional injections of 2000 IU of hCG or diluent alone (6 patients each; two lesions per patient). At the conclusion of therapy, the lesions were measured, their gross appearance assessed, and biopsy specimens evaluated. RESULTS: A.P.L. (Wyeth-Ayerst), which had the most in vitro activity against Kaposi's sarcoma cell lines, was selected for the clinical investigation. Treatment with A.P.L. was well tolerated at all doses. In the cohorts given 250, 500, 1000, and 2000 IU, 1, 5, 5, and 10 of the 12 injected lesions responded, respectively (P=0.03 for trend). Complete tumor regression was observed in one lesion each at the 250-IU and 500-IU doses, in two lesions given the 1000-IU dose, and in five lesions given the 2000-IU dose. In the double-blind study, none of the 12 lesions in the six patients injected with diluent had responses, as compared with 10 of the 12 lesions in the six patients injected with hCG (P=0.015). Microscopical evidence of apoptosis was observed only in hCG-treated lesions. The percentage of cells that died increased in a dose-dependent manner (P<0.001). Serum levels of follicle-stimulating hormone (P=0.002) and luteinizing hormone (P=0.001) declined after the last injection of hCG, but there was no effect on these hormones in the diluent-treated patients. CONCLUSIONS: The intralesional injection of hCG induces the regression of AIDS-related Kaposi's sarcoma lesions in a dose-dependent manner. The response of these tumors appears to be mediated by the induction of apoptosis.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Gonadotropina Coriônica/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Animais , Apoptose/efeitos dos fármacos , Gonadotropina Coriônica/administração & dosagem , Método Duplo-Cego , Gonadotropinas Hipofisárias/sangue , Humanos , Injeções Intralesionais , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Sarcoma de Kaposi/sangue , Sarcoma de Kaposi/patologia , Testosterona/sangue , Resultado do Tratamento , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Interleukin-10 (IL-10) is an acid-sensitive protein of 35 kD that has pleiotropic effects including inhibition of cytotoxic T-cell response, induction of major histocompatibility complex type II in B lymphocytes, induction of B-cell growth and differentiation, and autocrine growth factor activity in monocytes. We and others have shown that IL-10 is produced spontaneously by blood mononuclear cells from human immunodeficiency virus-seropositive patients. In an attempt to ascertain the potential role of IL-10 in acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma, we evaluated the expression of human IL-10 in both tumor-derived B-cell lines and primary tumor cells. Expression of human IL-10 (hIL-10) mRNA and protein was detected in four of five cell lines examined. An IL-10 antisense oligonucleotide inhibited IL-10 mRNA expression and IL-10 protein production. The proliferation of all B-cell lines was inhibited by an antisense oligonucleotide in a dose-dependent manner that was abrogated by the addition of recombinant hIL-10 protein. No effect of antisense oligonucleotide was observed in the B-cell line not producing hIL-10. Evaluation of primary tumor cells from patients with AIDS-lymphoma cells showed similar production and response to IL-10. These data suggest an autocrine growth mechanism for IL-10 in AIDS-related lymphoma cells and that IL-10 may be important in its pathogenesis.
Assuntos
Interleucina-10/biossíntese , Linfoma Relacionado a AIDS/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Sequência de Bases , Divisão Celular/efeitos dos fármacos , Humanos , Linfoma Relacionado a AIDS/patologia , Dados de Sequência Molecular , Oligonucleotídeos Antissenso/farmacologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Proteínas Recombinantes/farmacologia , Células Tumorais CultivadasRESUMO
BACKGROUND: Infection with the human T-cell lymphotropic virus type I, a retrovirus, can cause a distinctive cancer, adult T-cell leukemia-lymphoma. The median survival of patients with the acute and lymphomatous forms of the disease is short, despite the use of cytotoxic chemotherapy. METHODS: We treated 19 patients with acute or lymphomatous forms of adult T-cell leukemia-lymphoma with oral zidovudine (200 mg five times daily) and interferon alfa (Intron A, 5 to 10 million units subcutaneously each day). Seven of these patients had either relapsed after multiagent cytotoxic chemotherapy or failed to respond to that treatment. RESULTS: Major responses were achieved in 58 percent of the patients (11 of 19), including complete remission in 26 percent (5 of 19). Four patients in whom prior cytotoxic therapy had failed had major responses, two of which were complete remissions. Six patients have survived for more than 12 months, with the longest remission since the discontinuation of treatment lasting more than 59 months. CONCLUSIONS: The combination of zidovudine and interferon alfa has activity against adult T-cell leukemia-lymphoma, even in patients in whom prior cytotoxic therapy has failed. This regimen should be evaluated further for its role in the treatment of adult T-cell leukemia-lymphoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon-alfa/administração & dosagem , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Zidovudina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento , Zidovudina/efeitos adversosRESUMO
PURPOSE: Since liposomal encapsulation of anticancer drugs may enhance antitumor activity while reducing toxicity in vitro, we evaluated liposomally encapsulated daunorubucin (DaunoXome; Vestar, Inc, San Dimas, CA) for safety, pharmacokinetics, and potential efficacy in patients with AIDS-related Kaposi's sarcoma (AIDS-KS). PATIENTS AND METHODS: Forty patients with advanced AIDS-KS were accrued. Successive cohorts received DaunoXome at doses of 10, 20, 30, and 40 mg/m2 given once every 3 weeks, and 40, 50, and 60 mg/m2 given once every 2 weeks. Selected KS and solid-tumor patients underwent pharmacokinetic evaluation. RESULTS: The area under the plasma concentration curve (AUC) ranged from 16.9 micrograms.h/mL to 375.3 micrograms./mL and the alpha half-life ranged from 7.8 to 8.3 hours at 10 mg/m2 to 60 mg/m2, respectively. Both pharmacokinetic profiles were significantly better compared with free daunorubicin. DaunoXome was well tolerated with no significant alopecia, mucositis, or vomiting. Neutropenia (< 1,000/microL occurred in 17% of cycles and was severe (< 500/microL) in only 2%. Anemia and thrombocytopenia were uncommon. Other adverse events included mild to moderate fatigue, nausea, and diarrhea. Even after cumulative doses greater than 1,000 mg/m2, no significant declines in cardiac function were observed. Twenty-two patients who received 50 and 60 mg/m2 were assessable for tumor response; 12 (55%) had a partial response (PR) or clinical complete response (CR). The median survival duration in all patients was 9 months. Prognostic factors for short survival were low CD4 lymphocyte counts (P = .004) and prior anthracycline therapy (P = .02). CONCLUSION: DaunoXome has an improved pharmacokinetic profile compared with free daunorubicin, and is well tolerated. DaunoXome can be given safely at doses up to 60 mg/m2 every 2 weeks and has significant antitumor activity in patients with AIDS-KS.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Daunorrubicina/administração & dosagem , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Estudos de Coortes , Daunorrubicina/efeitos adversos , Daunorrubicina/farmacocinética , Portadores de Fármacos , Feminino , Meia-Vida , Humanos , Lipossomos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Prognóstico , Indução de Remissão , Sarcoma de Kaposi/etiologia , Sarcoma de Kaposi/mortalidade , Taxa de SobrevidaRESUMO
OBJECTIVE: To determine the toxicity and maximum tolerated dose of doxorubicin (adriamycin) in combination with fixed doses of bleomycin, vincristine (ABV) and zidovudine in patients with advanced AIDS-related Kaposi's sarcoma. PATIENTS AND METHODS: Twenty-six HIV-seropositive men with Kaposi's sarcoma were treated daily with 100 mg zidovudine orally every 4 h, along with combination chemotherapy using bleomycin 10 U/m2 and vincristine 1.4 mg/m2 (maximum, 2 mg) given intravenously in 2-week cycles. In addition, three successive cohorts of eight patients received escalating doses of doxorubicin each beginning with no doxorubicin (level I), doses of 10 mg/m2 (level II), and 15 mg/m2 (level III). RESULTS: The major dose-limiting toxicity experienced with the combination therapy was severe neutropenia in eight patients, four of whom received level III doxorubicin (15 mg/m2). Therefore, 10 mg/m2 of doxorubicin in combination with zidovudine and BV chemotherapy was defined as the maximum tolerated dose. Other dose-limiting toxicities included neuropathy (n = 2), cutaneous toxicity associated with bleomycin (n = 1), and diarrhea (n = 1). Seventeen patients (71%; 95% confidence interval, 46-85) experienced either partial (n = 13) or clinical complete remission (n = 4) to therapy after a median of five cycles (range, 2-9). CONCLUSION: The maximum tolerated dose of doxorubicin is 10 mg/m2 when given in combination with zidovudine and BV chemotherapy. Response rates observed with the combined antiretroviral and chemotherapy regimen are similar to those previously reported with ABV chemotherapy alone.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/etiologia , Zidovudina/administração & dosagem , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Bleomicina/administração & dosagem , Medula Óssea/efeitos dos fármacos , Contagem de Linfócito CD4 , Estudos de Coortes , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Tolerância a Medicamentos , Humanos , Masculino , Neutropenia/induzido quimicamente , Parestesia/induzido quimicamente , Vincristina/administração & dosagemRESUMO
Retinoids have anti-tumor activity in several malignant and premalignant conditions. Since Kaposi's sarcoma is regulated by steroid hormones both in vivo and in vitro, we hypothesized that retinoids may have anti-tumor effects in AIDS-related Kaposi's sarcoma. Thus, 27 patients with mucocutaneous, non-visceral AIDS-related Kaposi's sarcoma were treated with all-trans retinoic acid (tRA). Poor tolerance was observed at the initial starting dose of 150 mg/m2, and thus subsequent patients were treated using a weekly dose escalation, starting with 45 mg/m2 (given daily, in subdivided doses), to the target dose of 150 mg/m2 (given daily in three subdivided doses). Nearly half (46%) of the patients had extensive mucocutaneous disease with over 25 lesions. No patient had received prior cytotoxic chemotherapy. Ten patients had CD4 lymphocytes of 200/mm3 or greater (strata I); and 17 had under 200/mm3 CD4 lymphocytes (strata II). The median of the average daily tRA dose administered was 150 mg (90 mg/m2; there was no significant difference in the dose tolerance between the two strata). Adverse effects consisted of transient mild to moderate headaches in 65% of patients, mild to moderate skin dryness and cheilitis in 61%, and nausea and vomiting in 31%. Hematologic toxicities included hypertriglyceridemia in 62%, anemia in 23%, and neutropenia in 23%. Partial response to therapy was observed in 4/24 (17%) evaluable patients, occurring after 12, 20, 24, and 28 weeks of therapy, and lasting 4-24 weeks. Three responders had baseline CD4 lymphocyte counts < 200/mm3. Three additional patients experienced reduction in measured indicator lesions of greater than 25% but less than 50%, and seven patients experienced disease stabilization of 16 weeks or greater. In evaluable patients, the median time to disease progression was 22 weeks and the overall median survival in all patients was 27.3 months. No significant changes in CD4 lymphocyte counts, p24 antigen, and beta 2 microglobulin were observed over time. However, a statistically significant increase was observed in soluble IL-2 receptor levels while on tRA (p = 0.037). We conclude that tRA has activity in patients with mucocutaneous AIDS-related Kaposi's sarcoma with acceptable toxicity. tRA has immunological effects without upregulation of HIV parameters. Additional studies in combinations or with more active retinoids are warranted.