RESUMO
In this Phase I study, the maximally tolerated doses (MTDs) of i.p. iododeoxyuridine (IdUrd) alone and in combination with i.v. calcium leucovorin (LV) were determined. The pharmacokinetics and pharmacological advantage of IdUrd were evaluated, and flow cytometric analysis allowed examination of the extent of incorporation of IdUrd into tumor cells with and without the addition of i.v. LV. Thirty-nine patients with advanced neoplasms primarily confined to the peritoneal space were enrolled in a dose-escalation trial using 4-h dwells of IdUrd administered i.p. daily for 4 days with and without an i.v. infusion of LV 500 mg/m2/day for 4.5 days. Twenty-three patients received single-agent therapy, and 13 patients received i.p. IdUrd in combination with i.v. LV. The MTD of single-agent IdUrd administered on this schedule was 4125 mg/m2/day for 4 days; and that of the IdUrd in combination was 3438 mg/m2/day. Dose-limiting toxicities were myelosuppression and stomatitis. During the period of the dwell, the peritoneal AUC (area under the curve) of IdUrd exceeded the plasma AUC of IdUrd by one or two orders of magnitude in all patients at all doses tested; there was a possible effect of LV on peritoneal AUC. The geometric mean pharmacological advantage (AUCperitoneal/ AUCplasma) was 181 at 625 mg/m2/day and 90 at 4538 mg/m2/day. Flow cytometric analysis suggests saturation of IdUrd measured in DNA at the 2500-3125 mg/m2 dose level, without an increase after the addition of LV. Twelve patients received 4-12 courses of therapy. One patient with recurrent ovarian cancer who received 16 courses of therapy experienced complete resolution of her ascites, near normalization of CA-125 levels, and improved quality of life; two patients with high-risk tumors receiving "adjuvant" therapy are disease-free at 3 and 6 years after treatment; other patients experienced transient clearing of ascites. The recommended Phase II dose of i.p. IdUrd using a 4-h dwell daily for 4 days is 3750 mg/m2/day alone or 3125 mg/m2/day in combination with continuous i.v. LV at 500 mg/m2/day for 4.5 days. Although flow cytometric data suggest that DNA incorporation of IdUrd is not affected by the addition of LV, the cytotoxicity of the combination regimen may be increased due to LV-enhanced, IdUrd-related inhibition of thymidylate synthase. For this reason, we recommend that efficacy studies of the combination continue in parallel with studies of IdUrd alone.
Assuntos
Antídotos/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Idoxuridina/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Antígeno Ca-125/sangue , DNA de Neoplasias/metabolismo , Esquema de Medicação , Quimioterapia Combinada , Feminino , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Idoxuridina/efeitos adversos , Idoxuridina/farmacocinética , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Peritoneais/sangueRESUMO
PURPOSE: To increase the activity of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) through further biochemical modulation and study the pharmacologic interaction of 5-FU and interferon alfa-2b (IFN). PATIENTS AND METHODS: Escalating doses of IFN (0.5 to 4.0 x 10(6) U/m2/d x 6) were added to cisplatin 100 mg/m2, continuous infusion 5-FU 800 or 640 mg/m2/d x 5, and leucovorin 100 mg orally every 4 hours. Forty-eight previously untreated patients with locoregionally advanced head and neck cancer received up to three cycles of PFL-IFN. RESULTS: Twenty-one patients were treated during a phase I cohort study. Dose-limiting mucositis was seen with 800 mg/m2/d of 5-FU and 0.5 x 10(6) U/m2/d of IFN. After decreasing the 5-FU dose to 640 mg/m2/d, the maximally tolerated dose (MTD) of IFN was 2.0 x 10(6) U/m2/d. Mucositis and myelosuppression were dose-limiting. Of 34 patients treated at this MTD, 56% (95% confidence interval, 39% to 73%) had a complete remission. There was no correlation between 5-FU clearance and IFN dose. Pharmacodynamic analyses at the MTD showed that older age, female sex, and higher 5-FU area under the time versus concentration curve (AUC) were associated with lower nadir counts and/or increased mucositis. Seven patients with diabetes mellitus had significantly increased myelosuppression, serum creatinine, hypocalcemia, higher 5-FU concentrations, and lower 5-FU clearance compared with nondiabetics. CONCLUSION: The recommended doses for PFL-IFN are 640 mg/m2/d for 5-FU and 2.0 x 10(6) U/m2/d for IFN. Sex, age, 5-FU AUC, and diabetes mellitus may have an impact on the pharmacodynamics of this regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/administração & dosagem , Complicações do Diabetes , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Proteínas Recombinantes , Análise de Regressão , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the activity of two cycles of high-dose ifosfamide, carboplatin, and etoposide (ICE) with autologous hematopoietic progenitor cell support (aHPCS) in patients with poor-prognosis, chemotherapeutically sensitive germ cell cancer. PATIENTS AND METHODS: Twenty patients with germ cell tumor who had persistent disease or relapse from standard-risk or high-risk presentation were entered on this pilot study. The entry criteria included relapsed gonadal and extragonadal germ cell cancer unlikely to be cured by standard salvage therapy but without proven refractoriness to chemotherapy. Treatment consisted of two cycles of ICE chemotherapy with mesna uroprotection and aHPCS. On the first cycle, ifosfamide (IFX), 2 gm/m2; carboplatin, 400 mg/m2; and etoposide, 20 mg/kg, were administered on days -6, -5, and -4. On the second cycle, the doses and schedule of carboplatin and etoposide were identical, and patients with normal renal function received additional IFX, 2 g/m2 on day -3 and 1 g/ m2 on day -2. Mesna, 600 mg/m2 every 6 hours, was given until 24 hours following the final dose of IFX on each cycle, and autologous bone marrow and/or peripheral stem-cells were infused on day 0. RESULTS: All twenty patients are assessable for toxicity and current disease status. Two patients received only one cycle of therapy, one because of the development of active hepatitis C following cycle 1, and one because of renal insufficiency. No patient died as a result of protocol therapy, and no patient developed debilitating peripheral neuropathy, symptomatic hearing loss, or severe renal insufficiency requiring dialysis. The median time to recovery of > or = 500 neutrophils/microL and platelets > or = 50,000/microL was day +11 and day +15, respectively. The median maximum creatinine was 1.6 mg/dL on each treatment cycle, and there was no other significant organ toxicity. With a median follow-up of 45 months, nine patients are alive and disease-free following protocol chemotherapy. One patient with embryonal cancer developed progressive pulmonary metastases 3 months after completing high-dose therapy, underwent complete resection of lung metastases, and remains disease-free at 63+ months. Eight patients are continuously disease free at 23+ to 70+ months after protocol therapy. Eleven patients died of progressive disease between 4 and 23 months following completion of treatment. CONCLUSION: These results compare favorably to other studies in similarly selected patients undergoing salvage therapy with one or two cycles of chemotherapy containing high-dose carboplatin and etoposide with or without cyclophosphamide (CTX) or IFX. The excellent safety and tolerability profile of this regimen and its encouraging activity in poor-prognosis patients make it worthy of further study as part of initial therapy in randomized protocols for high-risk disease and early in the treatment of relapsed germ cell cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Germinoma/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Adulto , Carboplatina/administração & dosagem , Terapia Combinada , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Germinoma/sangue , Germinoma/cirurgia , Humanos , Ifosfamida/administração & dosagem , Masculino , Neoplasias do Mediastino/tratamento farmacológico , Mesna/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Projetos Piloto , Neoplasias Retroperitoneais/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológicoRESUMO
PURPOSE: To examine the predictive value of tumor- and treatment-specific prognostic indicators of relapse-free survival (RFS) and overall survival (OS) in patients with high-risk breast cancer (HRBC) treated with high-dose chemotherapy (HDCT) and stem-cell rescue. PATIENTS AND METHODS: Between June 1989 and September 1994, 114 patients with HRBC (stage II with > or = 10 axillary lymph nodes involved, stage IIIA, and stage IIIB inflammatory carcinoma) received adjuvant chemotherapy followed by HDCT with etoposide, cyclophosphamide, and either doxorubicin (CAVP) or cisplatin (CCVP). Variables analyzed included stage, tumor size, number of axillary nodes involved, grade and receptor status, and types of adjuvant chemotherapy and radiation therapy and HDCT. RESULTS: With a median follow-up time of 46 months (range, 23 to 93), Kaplan-Meier estimates of 3.5-year OS for stage II, IIIA, and IIIB HRBC are 82% (95% confidence interval [CI], 67% to 97%), 79% (95% CI, 67% to 91%), and 72% (95% CI, 53% to 91%); RFS estimates are 71% (95% CI, 56% to 85%), 57% (95% CI, 43% to 72%), and 50% (95% CI, 29% to 71%) irrespective of the HDCT regimen. In univariate analysis, the risk of relapse was lower for patients with progesterone receptor (PR)-positive tumors (risk ratio [RR], 0.43; 95% CI, 0.22 to 0.81; P = .01) and higher for patients with inflammatory carcinoma (RR, 2.20; 95% CI, 1.02 to 4.76; P = .05). OS was better for patients with PR (RR, 0.16; 95% CI, 0.05 to 0.55; P = .003) and estrogen receptor (ER)-positive tumors (RR, 0.42; 95% CI, 0.17 to 1.02; P = .05); OS was worse for patients with high-grade primary tumors (RR, 4.08; 95% CI, 1.21-13.7; P = .02). In multivariate analysis, PR positivity was associated with improved RFS (P = .01) and OS (P = .001). CONCLUSION: HDCT in selected patients with HRBC is safe and warrants further evaluation. Patients with receptor-negative, high-grade, or inflammatory tumors require improvement in their therapeutic options. Better assessment of the role of HDCT awaits completion of ongoing randomized trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
The purpose of this study was to determine the maximally tolerated dose of doxorubicin administered during two cycles of intensive chemotherapy with cyclophosphamide and doxorubicin without stem cell support in patients with advanced cancer and to assess the cumulative cardiac toxicity of the regimen by noninvasive radionuclide imaging and by pre-and postchemotherapy endomyocardial biopsies. Thirty-eight patients (thirty-six with high risk or metastatic breast cancer) were treated in a dose-escalation trial using a fixed dose of i.v. cyclophosphamide (4.2 g/m2) administered over 2 h on day 5 and escalating doses of doxorubicin (50-175 mg/m2) given as a 96-h continuous i.v. infusion on days 1-4, using Filgrastim (granulocyte colony-stimulating factor) for hematological support beginning on day 6. All patients underwent pretreatment, and 28 patients underwent postchemotherapy endomyocardial biopsies. Twenty-nine of 38 patients received two cycles of treatment (median number of days between cycles, 44; range, 34-62). Twenty-one patients had received doxorubicin previously at cumulative dose levels =150 mg/m2; all patients had pretreatment endomyocardial biopsy scores less than 1. One patient treated at the highest dose level of doxorubicin (175 mg/m2) developed symptoms of mild congestive heart failure following two cycles of chemotherapy. Pre- and posttreatment radionuclide ejection fractions were 65 and 45%, respectively; this patient had a posttreatment endomyocardial biopsy score of 1 (damage to <5% of myocytes). One additional patient at this dose level had an asymptomatic biopsy score of 1, with a decrease in ejection fraction from 62 to 43%; this recovered to 58% 5 months after completion of chemotherapy. Six additional patients treated at lower dose levels had abnormal posttreatment endomyocardial biopsies without abnormal posttreatment ejection fractions. Nine patients received only one cycle of chemotherapy: five patients due to decreased cardiac ejection fraction following cycle 1 (two of these patients had normal endomyocardial biopsies, and two patients had biopsy scores of 1); one patient secondary to tumor progression following cycle one; one patient due to persistently detectable Clostridium difficile toxin in the stool; one patient refused cycle two; and one patient died following cycle one of complications related to sepsis. A single patient experienced a grand mal seizure associated with orthostatic hypotension, which was considered the dose-limiting toxicity. The median duration (over two cycles) of granulocytopenia (absolute granulocyte count <500/microliter) at the maximally tolerated dose level of 150 mg/m2 was 8.5 days (range, 5-13 days), and the median duration of thrombocytopenia (platelets <20,000/microliter) was 2.5 days (range, 0-9 days). The median duration of hospitalization including chemotherapy administration was 23 days (range, 19-36 days). Other toxicities included stomatitis, fever, diarrhea, and emesis. One patient developed acute leukemia 54 months posttreatment. We conclude that two courses of high-dose cyclophosphamide and doxorubicin using granulocyte colony-stimulating factor are feasible and safe with tolerable myocardial toxicity as evidenced by serial endomyocardial biopsies. The dose-limiting toxicity encountered was a grand mal seizure. The recommended Phase II dose is doxorubicin 150 mg/m2 administered as a 96-h infusion on days 1-4, with cyclophosphamide 4. 2 g/m2 on day 5 and G-CSF 5 microgram/kg/day started on day 6 and administered until the total WBC is above 10,000/microliter for three consecutive days.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Estudos de Viabilidade , Feminino , Filgrastim , Imagem do Acúmulo Cardíaco de Comporta , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Humanos , Infusões Intravenosas , Metástase Linfática , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas RecombinantesRESUMO
This study was performed in order to evaluate the toxicities, progression-free and overall survival of patients with responsive residual or recurrent ovarian cancer treated with high-dose chemotherapy. Twenty-seven patients were treated. Doxorubicin, 165 mg/m(2) over 96 h (days -12 to -8), etoposide 700 mg/m(2) every day x3 (days -6 to -4), and cyclophosphamide 4.2 g/m(2) on d -3 was followed by stem cells and granulocyte colony-stimulating factor. The median days of granulocyte count <500/microl was 14 (range 10-42) and platelets <20,000/microl was 13 (range 2-80). Median numbers of red cell and platelet transfusions were 15 (5-16) and 14 (4-103). Toxicity included mucositis requiring narcotic analgesia in all patients. Asymptomatic decreases in ejection fraction to values <50% were observed in four patients. No clinical congestive heart failure was observed. One death due to sepsis was observed. Median progression-free survival is 7.5 months (1.0-56 months); five patients remain alive, two of whom remain progression-free at 19.5 and 24.5 months post transplant. Median overall survival is 14.0 months (1-68 months). We conclude that high-dose anthracyclines may be safely administered to ovarian cancer patients. The short overall and progression-free survivals observed in our population suggest that this combination is not optimal.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/análise , Antígeno Ca-125/análise , Carcinoma/sangue , Carcinoma/mortalidade , Carcinoma/cirurgia , Carcinoma/terapia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/terapia , Ovariectomia , Análise de Sobrevida , Transplante Autólogo , Falha de Tratamento , Resultado do TratamentoRESUMO
We analyzed the occurrence of putative risk factors for postoperative infection in 338 patients who underwent emergency laparotomy for penetrating abdominal injury. Mortality was 3%, with nine of ten deaths directly related to infectious complications. Gunshot wounds and colon injuries occurred more frequently in the patients who died than in survivors. Stepwise discriminant analysis revealed that transfusion requirement, length of operation, age, and the penetrating abdominal trauma index were the most significant risk factors for any infection. Other risk factors examined (shock, number of organs injured, mode of injury, and chest injury) did not contribute any additional information. Colon injury was more prevalent in patients with trauma-related infections than in those with nosocomial infections.
Assuntos
Traumatismos Abdominais/cirurgia , Infecções Bacterianas/etiologia , Laparotomia , Infecção dos Ferimentos/etiologia , Ferimentos Penetrantes/cirurgia , Traumatismos Abdominais/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Colo/lesões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Risco , Ferimentos por Arma de Fogo/complicações , Ferimentos Penetrantes/complicaçõesRESUMO
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: 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
The use of cytokines in head and neck cancer is increasingly under investigation. Clinical trials have tested the interferons, interleukin-2 and other cytokines as single agents and in various combinations. The addition of interferon to the cisplatin and 5-fluorouracil (5-FU) regimens (with and without leucovorin) has been explored. A randomized international trial comparing cisplatin and 5-FU with cisplatin, 5-FU and interferon-alpha 2b is in progress.
Assuntos
Antineoplásicos/uso terapêutico , Citocinas/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Interferons/uso terapêutico , Interleucina-2/uso terapêutico , Animais , Terapia Combinada , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interferon Tipo I/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
Chemotherapy for head and neck cancer is being actively investigated. Trials of cisplatin, infusional fluorouracil, and other new agents highlight the need for better therapies for patients with recurrent disease. Induction chemotherapy, concomitant chemoradiotherapy, and rapid-sequence combined therapy have been shown to be feasible treatments with encouraging results. Rapidly alternating chemoradiotherapy has been shown to result in a survival benefit compared with radiotherapy alone. Biologic therapy, including interferon and interleukin-2, also merits future evaluation in clinical trials.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Terapia Combinada , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The role of chemotherapy in the management of patients with head and neck cancer continues to evolve. Single-agent methotrexate or cisplatin, or the combination of cisplatin and infusional fluorouracil can be considered standard therapy for patients with recurrent disease. Neoadjuvant chemotherapy is being actively pursued. Although enhanced survival has not yet been demonstrated, the goal of organ preservation has been achieved for patients with laryngeal cancer. Because of the high incidence of locoregional failure, concomitant chemoradiotherapy is also under investigation. This treatment approach has already been suggested to result in prolonged survival in randomized studies and holds promise for the future.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Terapia Combinada , Fluoruracila/administração & dosagem , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Indução de Remissão , Análise de Sobrevida , Resultado do TratamentoRESUMO
We evaluated the effects of various schedules of peripheral blood stem cell (PBSC) reinfusion, granulocyte colony-stimulating factor (G-CSF) priming, and CD34+ enrichment on hematopoietic recovery in 88 patients with advanced breast cancer treated with high-dose chemotherapy, consisting of cisplatin 250 mg/m2, etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg. PBSC (> or = 7.5 x 10(8) nucleated cells/kg) were collected following priming with G-CSF and were either immediately cryopreserved (48 patients; cohorts A and B) or were first processed for CD34+ enrichment (40 patients; cohorts C and D). Patients in cohorts A and C received PBSC on day 0; patients in cohorts B and D received 25% of their nucleated cells on day -2 and 75% on day 0 (split reinfusion). Patients in cohorts A, B, and C were primed with G-CSF 10 micrograms/kg, subcutaneously (SC), once a day; patients in cohort D were primed with 5 micrograms/kg G-CSF, SC, twice daily (bid). Bid administration of G-CSF yielded 2.3 to 4.7 x higher numbers of CD34+ cells in the PBSC product than the same total dose given once a day (P = .002). Reinfusion of 25% of unselected PBSC on day -2 (median, 2.26 x 10(8)/kg nucleated cells [range, 1.7 to 3.3 x 10(8)/kg]) with the remaining cells reinfused on day 0 resulted in earlier granulocyte recovery to > or = 500/microL when compared with reinfusion of all stem cells on day 0 (group B, median of 8 days [range, 7 to 11] v group A, 10 days [range, 8 to 11], P = .0003); no schedule-dependent difference was noted in reaching platelet independence (group B, 11.5 days [range, 5 to 21]; group A, 12 days [range, 8 to 24], P = not significant). Split schedule reinfusion of CD34(+)-selected PBSC did not accelerate granulocyte recovery. In groups D and C, the median number of days to granulocyte recovery was 12 (range, 8 to 22) and 11.5 (range, 9 to 13); patients became platelet independent by day 15 (range, 6 to 22) and 14 (range, 12 to 23), respectively. CD34(+)-selected PBSC rescue decreased the incidence of postreinfusion nausea, emesis, and oxygen desaturation in comparison to unselected PBSC reinfusion (P < or = .005 for each). Hematopoietic recovery may be accelerated by earlier reinfusion of approximately 2.26 x 10(8)/kg unselected nucleated cells. Earlier recovery may be triggered by components other than the progenitors included in the CD34+ cell population. Sustained hematopoietic recovery can also be achieved with CD34(+)-selected PBSC alone. Dosing of G-CSF on a bid schedule generates higher CD34+ cell yield in the leukapheresis product. Whether even earlier "sacrificial" reinfusion of approximately 2 x 10(8)/kg unselected nucleated cells concomitant with the administration of high-dose chemotherapy would reduce the duration of absolute granulocytopenia further while initiating sustained long-term hematopoietic recovery will require further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/terapia , Carcinoma/terapia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Adulto , Antígenos CD34 , Contagem de Células Sanguíneas , Separação Celular , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Pessoa de Meia-IdadeRESUMO
We evaluated the feasibility of tandem-cycle high-dose chemotherapy (HDCT) with cisplatin, melphalan, and peripheral blood progenitor cells (PBPCs). Fifty patients with high-risk primary (n = 17) or stage IV breast cancer (n = 29) or other malignancies (n = 4) received 2 cycles of intravenous melphalan, 20 to 151.8 mg/m2, and cisplatin, 200 mg/m2, followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF. Starting at 40 mg/m2 of melphalan, patients also received PBPCs. Delayed platelet recovery defined the maximum tolerated dose (MTD) for melphalan at 101.2 mg/m2 per cycle. There were no treatment-related deaths. Cycle 2 was delivered at a median of 1.7 months after cycle 1; 72% of patients treated at the MTD received both cycles. Cycle 2 was omitted when patients refused it or had disease progression or toxicities, primarily prolonged thrombocytopenia. Complete response rates in stage IV breast cancer patients increased from 28% pre-HDCT to 55% after cycle 2. At a median follow-up of 4.6 years (range, 1.5-8.1 years), 11 of 29 patients with stage IV breast carcinoma were alive with 5-year projected progression-free and overall survival rates of 19% (95% confidence interval [CI], 7%-41%) and 39% (95% CI, 20%-62%), respectively. Five-year projected progression-free and overall survival rates for patients with stage IV breast cancer in complete response following HDCT versus all others were 35% (95% CI, 15%-70%) versus 0% (P = .01) and 61% (95% CI, 35%-91%) versus 10% (95% CI, 2%-60%) (P = .003; log-rank test), respectively. Estrogen-receptor positivity was predictive of reduced risk of progression (relative risk [RR], 0.25; 95% CI, 0.10-0.65; P = .003) and death (RR, 0.27; 95% CI, 0.10-0.72; P = .009) after adjusting for response status. Five-year projected relapse-free and overall survival rates were 71% (95% CI, 43%-96%) and 82% (95% CI, 56%-100%), respectively, for the 17 patients with high-risk primary breast cancer. Tandem-cycle high-dose melphalan and cisplatin with PBPCs is feasible. Preliminary data suggest significant activity in selected patients with stage IV responding breast carcinoma.