RESUMO
Cisplatin, alone or in combination with other chemotherapeutic agents, is relatively inactive against metastatic melanoma. Prior trials have demonstrated partial response (PR) rates of less than 10% with cisplatin alone. WR-2721 is an organic thiophosphate compound, which in the animal model, selectively protects normal tissues against the toxicity of cisplatin chemotherapy. During the course of a phase I trial of WR-2721 and cisplatin, objective PRs were noted in patients with far advanced metastatic melanoma. These observations led us to perform a phase II trial of WR-2721 and cisplatin. Thirty-six patients received 128 courses of WR-2721 before cisplatin (60 to 150 mg/m2). All patients had progressive disease before treatment. Objective PRs were observed in 19 of 36 evaluable patients (53%). Three additional patients had minor responses (MRs). PRs occurred in 53% of patients with prior chemotherapy (ten of 19). Sites of responding metastases were subcutaneous disease (15 of 19 patients), lymph nodes (16 of 21 patients), lung (four of ten patients), and liver (eight of 17 patients). The median duration of response was 4 months, with a mean of 4.5 months (range, 1 to 8 months). Transient nephrotoxicity was observed in less than 5% of courses. In all cases, renal function returned to normal within 1 to 2 weeks. Hematologic toxicity was mild and infrequent. Nine patients developed peripheral neuropathy following a median cisplatin dose of 670 mg/m2. Twenty patients experienced mild clinical hearing loss. These data suggest that WR-2721 may potentiate the antitumor activity of cisplatin in metastatic melanoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Amifostina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Avaliação de Medicamentos , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-IdadeRESUMO
The American Board of Internal Medicine (ABIM) has asked that directors of medical oncology training programs establish systems to evaluate, document, and substantiate the clinical competence of subspecialty trainees who seek certification. The Board defines the certificable medical oncologist at the completion of training as being competent to provide comprehensive and specialized medical care based on a high standard of demonstrated component skills. These skills clearly exceed those demonstrated by the certified internist. The goal of this expanded evaluation program is to ensure that the public and the profession can identify, through certification, physicians capable of providing a high standard of medical care.
Assuntos
Certificação , Competência Clínica/normas , Medicina Interna/educação , Oncologia/educação , Conselhos de Especialidade Profissional , Humanos , Estados UnidosRESUMO
WR-2721 S-2-(3-aminopropylamino) ethyl phosphorothioic acid, is an organic thiophosphate compound that in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Preliminary data from our controlled phase I trial of WR-2721 and cyclophosphamide suggested that WR-2721 protected against cyclophosphamide-induced granulocytopenia. Since variable drug doses and infusion rates were used in these early studies, we initiated a controlled phase II trial using constant drug doses to establish more precisely WR-2721's level of protection. Initially, 21 patients received 1,500 mg/m2 of cyclophosphamide alone and were retreated 4 weeks later after hematologic recovery was complete with 740 mg/m2 of WR-2721 before the same dose of cyclophosphamide. With WR-2721 pretreatment, 19 of 21 (90%) patients had improved WBC and granulocyte counts. The mean WBC increased from 1,760/mL with cyclophosphamide alone to 2,500/mL with WR-2721 pretreatment (P less than .0005). The mean granulocyte count increased from 541/mL on cyclophosphamide to 1,247/mL with WR-2721 and cyclophosphamide (P less than .0005). Following cyclophosphamide administration alone, neutropenic fevers developed in three patients. No patient experienced a febrile episode following WR-2721 and cyclophosphamide administration. Platelet nadirs below 100,000/mL were only noted in two patients treated with cyclophosphamide alone. Objective partial responses were observed in four of 19 (21%) patients with measurable or evaluable disease. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced hematologic toxicity.
Assuntos
Amifostina/uso terapêutico , Ciclofosfamida/toxicidade , Leucopenia/prevenção & controle , Neoplasias/tratamento farmacológico , Compostos Organotiofosforados/uso terapêutico , Idoso , Amifostina/toxicidade , Ciclofosfamida/uso terapêutico , Avaliação de Medicamentos , Humanos , Leucopenia/induzido quimicamente , Pessoa de Meia-IdadeRESUMO
PURPOSE: Despite modern therapy, patients with low-grade non-Hodgkin's lymphomas (NHLs) have a median survival of only 7 to 10 years. To determine factors that predict for short survival after relapse and thus to identify candidates for intensive investigational studies including bone marrow transplantation, we have analyzed the combined results of three Eastern Cooperative Oncology Group (ECOG) trials of initial chemotherapy for lymphoma. PATIENTS AND METHODS: All 466 patients who achieved initial complete response (CR) or partial response (PR) and had a subsequent relapse were evaluated (median follow-up, 12.6 years). Multivariate regression analysis within a training set (two thirds of cases) was verified in the remaining one-third (validation set) of cases. RESULTS: Age younger than 60 years, CR, and response duration were significantly associated with longer survival after relapse. Multivariate analysis developed a predictive model that identified shorter survival in patients greater than or equal to 60 years, regardless of CR or response duration. Patients younger than 60 years with an initial CR of more than 1 year had a median survival of 5.9 years, those with a PR of more than 1 year had a median survival of 4.2 years, and those with a CR or PR of less than or equal to 1 year, 2.4 years (P less than .0001). Even the most favorable group had a 10-fold greater mortality compared with age-adjusted United States population rates. CONCLUSIONS: These data suggest that patients with low-grade NHLs with a less than or equal to 1-year response period have poor survival after relapse and may be candidates for aggressive salvage therapy, including transplantation. Longer initial responses lead to better survival after relapse. Clinical trials seeking to demonstrate an advantage for new treatments including transplantation will require long follow-up and comparison to control populations for meaningful analysis.
Assuntos
Transplante de Medula Óssea , Linfoma não Hodgkin/cirurgia , Adulto , Feminino , Humanos , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Between July 1, 1981 and November 1, 1982, 45 patients with acute nonlymphocytic leukemia (age, greater than or equal to 70 years) were randomly assigned to receive induction chemotherapy using either daunorubicin, cytosine arabinoside, and 6-thioguanine in full dosage (F DAT) or an attenuated schedule of the same drugs (At DAT) as part of an Eastern Cooperative Oncology Group controlled trial. Forty patients were deemed evaluable, 20 on each arm. The overall complete remission (CR) rate for all patients in both arms was 28% (11/40). There was no significant difference in CR rates between the two arms. There were 12 early deaths (less than 60 days) in the F DAT arm compared with only five early deaths on the At DAT arm (P = .05). Due primarily to this early death rate, the median survival for the F DAT group was 29 days v 159 days for the At DAT groups (P = .02). The range of survival of the patients in CR for the At DAT group given either one or two cycles of induction therapy was 121 to 414 days, while the survival range for the F DAT CR patients was 121-186 + days. The median survival for those not achieving CR was 14 days for the F DAT group v 80 days for the At DAT (P less than .02). Fifty-nine percent of the At DAT patients spent greater than 100 days out of the hospital v 12% for the F DAT group. Attenuated chemotherapy with lower doses of DAT is the preferred induction regimen for elderly patients with acute nonlymphocytic leukemia since it causes fewer early deaths, allows a better quality of life, and yields survival times as durable as intensive therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia/tratamento farmacológico , Doença Aguda , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos como Assunto , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Esquema de Medicação , Coração/efeitos dos fármacos , Hemorragia/induzido quimicamente , Humanos , Leucemia/mortalidade , Qualidade de Vida , Distribuição Aleatória , Síndrome do Desconforto Respiratório/induzido quimicamente , Tioguanina/administração & dosagem , Tioguanina/efeitos adversosRESUMO
One hundred twenty-eight patients with purely nodular lymphocytic poorly differentiated lymphoma (NLPDL) without any prior therapy, entered on Eastern Cooperative Oncology Group protocol EST 2474, were analyzed for response, progression-free and overall survival. The restaged complete response rates with cyclophosphamide-prednisone (CP) (moderate regimen) of 54% compared favorably with those of the more intensive regimens; cyclophosphamide, vincristine, procarbazine and prednisone (COPP) (56%) and BCNU, cyclophosphamide, vincristine, and prednisone (BCVP) (53%). The toxicity of the regimens decreased from BCVP to COPP to CP. The median survival rate for the entire group was 7.8 years. Estimated progression-free survival at five years by regimen was COPP, 57%; BCVP, 26%; CP, 22% (P = .02). No other prognostic parameter significantly affected progression-free survival. In spite of the better progression-free survival of COPP-treated patients, the overall survival rates with the different induction regimens were similar. Maintenance therapy for patients in complete response at the end of induction therapy with periodic BCVP reinduction did not significantly affect the disease-free or overall survival. Cyclophosphamide-prednisone is a minimally toxic regimen effective in the treatment of NLPDL, but COPP, in view of its acceptable toxicity in this patient population and apparent superiority in providing a longer disease-free state, deserves further testing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carmustina/administração & dosagem , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Humanos , Leucopenia/induzido quimicamente , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Prognóstico , Distribuição Aleatória , Risco , Vincristina/administração & dosagemRESUMO
High-dose cytosine arabinoside ( HDARAC ) and 4'-(9 acridinylamino) methane sulfon -m-anisidine (m-AMSA) was administered as induction therapy to 40 patients with relapsed or refractory acute nonlymphocytic leukemia (ANLL) with the following results: 28 patients (70%) achieved complete remission, one patient achieved a partial remission; five patients died with hypoplastic bone marrows containing less than 5% blasts; four patients died with hypoplastic marrowing containing greater than 5% blasts; and three patients failed to achieve marrow aplasia and died without significant cytoreduction in percentage of blasts. Consolidation therapy was not used and maintenance therapy was given to less than 10% (three patients) of remission patients. The median duration of remission for all patients was 6.0 months and the median time for the complete remission patients exceeded eight months. This regimen has acceptable toxicity and the results are equivalent to those obtained from conventional induction therapy of de novo ANLL patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Idoso , Aminoacridinas/administração & dosagem , Aminoacridinas/efeitos adversos , Amsacrina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medula Óssea/efeitos dos fármacos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Toxidermias/etiologia , Hemorragia/induzido quimicamente , Humanos , Leucemia/mortalidade , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Recidiva , VômitoRESUMO
Data from four clinical trials conducted by the Eastern Cooperative Oncology Group (ECOG) were used to investigate the importance of bone marrow involvement as a prognostic factor in patients with non-Hodgkin's lymphoma (NHL). A total of 502 patients, 275 with nodular, poorly differentiated lymphocytic lymphoma (NLPD) and 227 with diffuse histiocytic lymphoma (DHL) or diffuse mixed-cell lymphoma (DML), were included in this analysis. Patients were separated into four categories: stage III, stage IV with bone marrow involvement (stage IV-M), stage IV without marrow involvement (stage IV-O), and stage IV with bone marrow and other organ involvement (stage IV-OM). Among the DHL and DML patients, the incidence of marrow involvement was 23%. However, stage IV-M patients had a prognosis that is similar to stage IV-O and stage IV-OM and worse than stage III patients. In contrast, the incidence of involvement with NLPD was 59% and patients with stage IV-M had a survival not different than stage III and not worse than stage IV-O and stage IV-OM. The results suggest that the current emphasis on bone marrow biopsy(s) as a routine diagnostic staging procedure for patients with NHL should be reevaluated. The necessity for this procedure in stage III patients with NLPD is not apparent from our data. One can still justify a bone marrow biopsy in stage I and II patients and can confirm the complete clinical response when all nodes have regressed in more advanced disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Linfoma não Hodgkin/patologia , Ensaios Clínicos como Assunto , Esquema de Medicação , Feminino , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/mortalidade , Masculino , Estadiamento de Neoplasias , Prognóstico , RiscoRESUMO
PURPOSE: To determine the efficacy of a biweekly paclitaxel and cisplatin regimen in patients with advanced breast carcinoma, which has previously been reported to produce an 85% response rate in such patients. PATIENTS AND METHODS: Sixteen patients with metastatic breast carcinoma who had relapsed after prior doxorubicin-containing adjuvant chemotherapy were treated with paclitaxel (90 mg/m2) by intravenous (i.v.) infusion over 3 hours followed by cisplatin (60 mg/m2) given by i.v. infusion over 1 hour on an outpatient basis. Treatment was repeated every 2 weeks if the absolute neutrophil count was > or = 750/microL and platelet count > or = 75,000/microL. After a maximum of eight cycles of paclitaxel/cisplatin, patients received biweekly paclitaxel alone (90 mg/m2 with dose escalation). Thirteen patients were assessable for response and all for toxicity. Nine of 13 patients assessable for response (69%) had at least three sites of metastases and 10 patients (77%) had visceral-dominant disease. RESULTS: Partial response occurred in three of 13 assessable patients (23%; 90% confidence interval, 7% to 49%). All responders had two or fewer sites of metastases. The median time to progression was 4.3 months and the median survival duration was 11.4 months. Patients received a median of seven cycles of therapy (range, two to 21). Severe and/or life-threatening toxicity occurred in 50% and 38%, respectively, and consisted primarily of granulocytopenia, anemia, and neuropathy. The trial was terminated after the first interim analysis as per its two-stage design, since it was unlikely that the response rate would exceed 70%. CONCLUSION: Biweekly paclitaxel/cisplatin is not likely to produce a response rate greater than 70% in patients with metastatic breast cancer who have relapsed after prior doxorubicin-containing adjuvant chemotherapy and who have multiple sites of metastases and/or visceral-dominant disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Neoplasias da Mama/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Análise de SobrevidaRESUMO
PURPOSE: To compare the efficacy of sequential mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) followed by doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus the MOPP/ABV hybrid regimen in advanced-stage Hodgkin's disease. PATIENTS AND METHODS: A total of 737 patients with previously untreated stages III2A, IIIB, IVA, or IVB Hodgkin's disease and patients in first relapse after radiotherapy were prospectively randomized to sequential MOPP-ABV or MOPP/ABV hybrid. Of 691 eligible patients, 344 received the sequential regimen and 347 received the hybrid. RESULTS: The overall response rate was 95%, with complete responses (CRs) in 79%: 83% on the MOPP/ABV hybrid and 75% on the sequential MOPP-ABVD arm (P = .02). With a median follow-up time of 7.3 years, the 8-year failure-free survival (FFS) rates were 64% for MOPP/ABV hybrid and 54% far sequential MOPP-ABVD (P = .01; 0.69 relative risk of failure, comparing MOPP/ABV hybrid v MOPP-ABVD). The 8-year overall survival rate was significantly better for the MOPP/ABV hybrid (79%) as compared with sequential MOPP-ABVD (71%) (P = .02; relative risk, 0.65). MOPP/ABV hybrid had significantly more life-threatening or fatal neutropenia and pulmonary toxicity than the sequential MOPP-ABVD arm, which was associated with significantly greater thrombocytopenia. Nine cases of acute myelogenous leukemia or myelodysplasia were reported on the sequential regimen as compared with only one on the hybrid (P = .01). CONCLUSION: MOPP/ABV hybrid chemotherapy was significantly more effective than sequential MOPP-ABVD. FFS and overall survival were significantly improved on the hybrid arm, which was also associated with a lower incidence of acute leukemia or myelodysplasia.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Masculino , Mecloretamina/administração & dosagem , Mecloretamina/efeitos adversos , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Procarbazina/administração & dosagem , Procarbazina/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Three hundred thirty-two eligible patients with advanced (Ann Arbor stage III or IV) non-Hodgkin's lymphoma of aggressive histologic subtype (Rappaport classification diffuse histiocytic [DH], diffuse poorly differentiated lymphocytic [DPDL], diffuse mixed [DM], or diffuse undifferentiated [DU]) were randomly assigned to receive induction chemotherapy with one of three intensive regimens in a clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG) between 1978 and 1983. Chemotherapy regimens consisted of cyclophosphamide, vincristine, prednisone, and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (COPA) administered in 3-week cycles; cyclophosphamide plus doxorubicin plus prednisone beginning day 1, with vincristine plus bleomycin day 15 of each 3-week cycle (COPA + Bleo); or cyclophosphamide plus doxorubicin plus procarbazine beginning day 1, and bleomycin plus vincristine plus prednisone beginning day 15 of each 4-week cycle (CAP-BOP). The median patient follow-up from study entry for patients still alive is 5 years. The three regimens were not significantly different with respect to complete response (CR) rates (43% to 46%), time to progression of malignant disease (median, 1.0 to 1.7 years), or survival (5-year survival, 34% to 45%), although duration of complete remission appeared to be shorter in patients receiving COPA (P = .03). COPA + Bleo and CAP-BOP were significantly more toxic than the COPA regimen. This study did not demonstrate any substantial therapeutic advantage associated with the addition of a fifth or sixth chemotherapy drug, or with treatment administered on a more frequent administration schedule, compared with the COPA regimen in this population of patients with advanced diffuse non-Hodgkin's lymphoma. The relatively small proportion of long-term disease-free survivors treated with COPA underscores the need for prospective clinical trials of new and more effective treatments for patients with these potentially curable tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bleomicina/administração & dosagem , Ensaios Clínicos como Assunto , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Estudos Prospectivos , Distribuição Aleatória , Vincristina/administração & dosagemRESUMO
PURPOSE: To determine the effectiveness of fluorouracil plus levamisole administered postoperatively to patients with resected stage II (Dukes' B2) colon cancer. PATIENTS AND METHODS: This randomized controlled clinical trial (INT-0035) was performed by National Cancer Institute-sponsored cancer clinical trials cooperative groups. Patients were assigned to observation only or to fluorouracil (450 mg/m2 intravenously [IV] daily for 5 days and, beginning at 28 days, weekly for 48 weeks) plus levamisole (50 mg orally three times daily for 3 days repeated every 2 weeks for 1 year). Cancer recurrence, survival, and treatment side effects were assessed. RESULTS: Three hundred eighteen eligible patients were analyzed with a median follow-up time of 7 years. Fluorouracil plus levamisole reduced the recurrence rate by 31%, although this trend was not statistically significant (P = .10). A total of 87 patients died: 43 on observation and 44 on fluorouracil plus levamisole. Disparity between effects on recurrence rate and overall survival is partially explained by a higher rate of non-colon cancer-related deaths on fluorouracil plus levamisole (15 v seven) and by the effects of salvage surgery with curative intent. Of seven patients with recurrence who were rendered disease-free by salvage surgery, six were on the observation arm. As was observed in patients treated with fluorouracil plus levamisole for stage III disease, toxicity was acceptable and compliance was excellent. CONCLUSION: Fluorouracil plus levamisole is tolerable and accepted as standard surgical adjuvant therapy for patients with stage III colon cancer, but the data from this study in stage II patients suggest a decreased relapse rate without a significant improvement in survival.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Neoplasias do Colo/cirurgia , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Levamisol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , PrognósticoRESUMO
Progestational agents, such as megestrol acetate and medroxyprogesterone acetate, are effective hormonal treatments for metastatic breast cancer in postmenopausal women. Clinical trials of these agents have demonstrated that 30% to 60% of patients will experience objective tumor response, depending on pretreatment prognostic variables. Although optimal doses and schedules have not been fully defined, current studies are investigating the therapeutic effectiveness of high-dose progestins. Toxicity of these drugs is mild and generally limited to weight gain related to their anabolic activity. Progestins are active second-line agents for metastatic breast cancer in postmenopausal women. In selected patients, they appear to be equivalent to tamoxifen as first-line therapy for metastatic disease. As more patients are exposed to prolonged adjuvant tamoxifen therapy, the role of progestins as first-line hormonal therapy at the time of relapse is likely to expand.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Medroxiprogesterona/análogos & derivados , Megestrol/análogos & derivados , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Antineoplásicos/efeitos adversos , Neoplasias da Mama/metabolismo , Feminino , Humanos , Medroxiprogesterona/efeitos adversos , Medroxiprogesterona/uso terapêutico , Acetato de Medroxiprogesterona , Megestrol/efeitos adversos , Megestrol/uso terapêutico , Acetato de Megestrol , Menopausa , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptores de Superfície Celular/metabolismo , Tamoxifeno/uso terapêuticoRESUMO
The toxicity of radiation and alkylating agent chemotherapy is in part related to free radical formation in DNA and associated proteins, which is enhanced by oxygen and other electron affinic compounds. During the Phase I clinical trials of WR-2721 and alkylating agent chemotherapy, venous blood samples were obtained prior to and immediately following the WR-2721 infusion. We have observed a marked increase in the oxygen saturation of venous blood following WR-2721 (430-910 mg/m2 at a rate of 15 mg/m2/minute). The mean venous PO2 (PvO2) rose from a baseline of 34.0 +/- 13.54 torr to a mean value of 54.60 +/- 12.47 torr (p less than 0.001). The percent venous oxygen saturation increased from 54.52 +/- 21.38% to 82.73 +/- 7.66%. The highest values generally occurred within the first 2 hours after the completion of the WR-2721 infusion. No significant differences were found between the pre and post WR-2721 values for either the venous pH, CO2, or bicarbonate levels. Despite increased PvO2, the patients' heart rates, blood pressures, or respiratory rates did not change pre and post WR-2721. No apparent differences were noted in the effects of WR-2721 or PvO2 when given at doses of 740 or 910 mg/m2. However, when WR-2721 (418-1100 mg/m2) was administered over 15 minutes, the PvO2 increased in only 8/13 courses. We postulated that the marked increase in venous blood oxygen concentration was secondary to one of the following mechanisms: 1) Increased affinity of hemoglobin for oxygen, 2) microcirculatory shunting, or 3) decreased tissue requirements for oxygen. In 12 patients oxygen-hemoglobin dissociation curves and intracellular red cell pH's were obtained before and after 740-910 mg/m2 of WR-2721. Despite the significant increase in oxygenation of venous blood after WR-2721, there were no changes in either oxygen-hemoglobin dissociation or intracellular red cell pH to account for this increase. The oxygen consumption of peripheral blood granulocytes was measured prior to and following 15 courses of WR-2721. A marked decrease in granulocyte oxygen consumption was observed in 6/8 patients who had a significant increase in PvO2 and only 1/7 patients who had either a decrease or no change in PvO2 after WR-2721. Our preliminary investigations suggest that the increased venous blood oxygen content may be secondary to a reduction in normal tissue oxygen consumption. WR-2721 may afford protection by both decreasing oxygen consumption and delivery to normal tissues and increasing intracellular sulfhydryls.
Assuntos
Amifostina/farmacologia , Compostos Organotiofosforados/farmacologia , Oxigênio/sangue , Protetores contra Radiação/farmacologia , Bicarbonatos/sangue , Dióxido de Carbono/sangue , Granulócitos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Consumo de Oxigênio , Pressão Parcial , Fatores de Tempo , VeiasRESUMO
Renal dysfunction is a well-known dose-limiting toxicity of cis-platinum. Previous studies demonstrated a 32% incidence of nephrotoxicity following a 100 mg/M2 single dose of cis-platinum with mannitol diuresis. WR-2721 is an aminothiol which in the animal model improves renal tolerance to cis-platinum by factors of 1.3 to 1.7. Phase I trials were initiated to establish the toxicity when WR-2721 was given prior to escalating doses of cis-platinum. Fifty-two patients received 161 courses of WR-2721 prior to cis-platinum (60-150 mg/M2) with mannitol and hydration. Nephrotoxicity, measured by twice weekly serum creatinines and monthly creatinine clearances, occurred in only 10/97 (10%) courses with 120 mg/M2 of cis-platinum. No patient experienced a creatinine elevation after 135 mg/M2 of cis-platinum. With 150 mg/M2 of cis-platinum, 6/17 (35%) courses were associated with transient nephrotoxicity. Five patients who developed transient creatinine elevations following 150 gm/M2 of cis-platinum were subsequently retreated with WR-2721 and cis-platinum (100 mg/M2) without nephrotoxicity. Bone marrow suppression was mild and infrequent. Mild to moderate peripheral neuropathies were noted in seven patients following cumulative cis-platinum doses ranging from 460-1160 mg/M2. Objective partial responses were observed in 26/45 (58%) patients with measurable or evaluable disease. Thus, there is no evidence that WR-2721 protects against the antitumor efficacy of cis-platinum in man. Compared to retrospective series, our data suggest that WR-2721 may provide some protection against platinum-induced nephrotoxicity and neurotoxicity. Controlled trials will be required to define the potential clinical benefit of WR-2721 and cis-platinum.
Assuntos
Amifostina/uso terapêutico , Cisplatino/uso terapêutico , Nefropatias/prevenção & controle , Neoplasias/tratamento farmacológico , Compostos Organotiofosforados/uso terapêutico , Cisplatino/efeitos adversos , Avaliação de Medicamentos , Humanos , Rim/efeitos dos fármacos , Nefropatias/induzido quimicamenteRESUMO
From 1978 to 1981, 46 patients received primary radiotherapy following excisional biopsy and axillary staging procedure for Stages I and II carcinoma of the breast. The patients were divided into 2 groups: 27 patients who received radiation and completed 12 cycles of adjuvant chemotherapy (CMF or CMFP) and 19 patients who received radiation alone. All patients received radiation to the breast and regional nodes (4600-5000 rad) and a boost to the site of the primary tumor (1500-2000 rad). Median follow-up from completion of radiation was 26 months in the non-adjuvant and 24 months in the adjuvant group with a range of 12 to 49 months. Cosmesis was judged to be good to excellent in 89% (17/19) of the patients receiving radiation alone and 81% (22/27) of the patients receiving adjuvant chemotherapy. Fair to poor cosmesis in the adjuvant group was attributed primarily to increased fibrosis and reduction of breast size. The single complication for which there was an increased incidence in the adjuvant group was arm edema (22 vs. 0%). The incidence of arm edema was unrelated to T stage, type of axillary surgical procedure, number of positive nodes, addition of prednisone or sequencing of chemotherapy. Further efforts should be directed towards minimizing complications and maximizing cosmesis without sacrificing relapse-free survival in patients receiving primary radiotherapy and adjuvant chemotherapy for early breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Braço , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Edema/etiologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Prednisona/administração & dosagem , Radioterapia de Alta Energia/efeitos adversosRESUMO
WR-2721 is an organic thiophosphate compound which in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Controlled Phase I trials of WR-2721 and cyclophosphamide were initiated to determine if WR-2721 protected against cyclophosphamide's hematologic toxicity. Fifteen patients received WR-2721 (450-1100 mg/m2) prior to cyclophosphamide (1200-1800 mg/m2) and were subsequently retreated 4 weeks later with the same cyclophosphamide dose alone. With WR-2721 pretreatment, 11/15 (73%) patients had improved WBC counts. The mean WBC increased from 1800/mm3 on cyclophosphamide alone to 2700/mm3 with WR-2721 + cyclophosphamide (p = 0.008). In 11 patients who had nadir differential counts performed, 7 (64%) demonstrated improved nadir granulocyte counts with WR-2721. The mean granulocyte count increased from 765/mm3 on cyclophosphamide to 1274/mm3 with WR-2721 + cyclophosphamide (p = 0.05). In the second trial, 25 patients received the reverse sequence: an initial dose of cyclophosphamide (1200-1800 mg/m2) alone, followed 4 weeks later by WR-2721 (450-1100 mg/m2) prior to the same dose of cyclophosphamide. With WR-2721 pretreatment, 12/25 (48%) patients had improved nadir WBC counts. The mean WBC increased from 1550/mm3 on cyclophosphamide alone to 1850/mm3 with WR-2721 + cyclophosphamide (p = 0.02), while the nadir granulocyte count increased from 449/mm3 to 844/mm3 (p = 0.001). No patient developed microscopic or gross hematuria or inappropriate antidiuretic hormone secretion. One patient developed mild thrombocytopenia. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced granulocytopenia, but the dose modification factors and degree of clinical benefit remain to be established. The current recommended WR-2721 dose for Phase II trials is 740 mg/m2 administered over 15 minutes.
Assuntos
Amifostina/uso terapêutico , Ciclofosfamida/uso terapêutico , Compostos Organotiofosforados/uso terapêutico , Adulto , Idoso , Agranulocitose/induzido quimicamente , Agranulocitose/prevenção & controle , Avaliação de Medicamentos , Quimioterapia Combinada , Humanos , Leucopenia/induzido quimicamente , Leucopenia/prevenção & controle , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Protetores contra Radiação/uso terapêuticoRESUMO
WR-2721 is a sulfhydryl compound which in the animal model improves renal tolerance to cis-platinum (DDP) by factors of 1.3 to 1.7. Phase I trials were initiated to establish the toxicity and dose modification factors when WR-2721 was given prior to escalating doses of DDP. Nineteen patients received 27 courses of WR-2721 (450-910 mg/m2) 20 minutes prior to DDP (50-120 mg/m2). Patients were prehydrated, but no mannitol or other diuretics were administered. Mild, transient nephrotoxicity was observed in only 2 of 15 courses of DDP 80-100 mg/m2 when WR-2721 was given prior to DDP. Although 5 of 9 patients treated with WR-2721 prior to 120 mg/m2 of DDP developed transient nephrotoxicity, their serum creatinines returned to normal baseline values within 1 to 2 weeks. Subsequently, the protocol was modified to include mannitol diuresis. Thirty-four courses of WR-2721 (740 mg/m2) prior to DDP 120-150 mg/m2 with mannitol diuresis were administered. Biweekly serum creatinine and monthly creatinine clearances have remained normal in all patients treated with 120 mg/m2 of platinum and WR-2721. Four of 10 patients treated with 150 mg/m2 of cis-platinum experienced transient nephrotoxicity 5-7 days after treatment. Mild ototoxicity was noted in 4 patients following 150 mg/m2 of DDP. WR-2721 does not appear to protect against the antitumor efficacy of DDP, as 57% of all patients achieved objective partial responses, lasting 1+ to 7+ months. Partial responses occurred in 3/4 (75%) of patients with melanoma and 7/10 (70%) patients with cancer of the head and neck. Compared to retrospective series, our data suggest that WR-2721 may provide some protection against platinum-induced nephrotoxicity, but the dose modification factors remain to be established.
Assuntos
Amifostina/uso terapêutico , Cisplatino/uso terapêutico , Compostos Organotiofosforados/uso terapêutico , Avaliação de Medicamentos , Quimioterapia Combinada , Humanos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Neoplasias/tratamento farmacológico , Protetores contra Radiação/uso terapêuticoRESUMO
The radioprotector with clinical potential, S-2-(3 aminopropylamino)-ethylphosphorothioic acid (WR-2721) is undergoing two Phase I trials. The objectives of these trials are 1) to determine the maximum tolerated dose (MTD) of WR-2721 in a single dose and 2) to determine the highest dose of WR-2721 that can be tolerated daily in the greatest number of fractions per week. A total of 65 patients have been treated. The single maximum tolerated dose has not yet been reached, though 740 mg/m2 is well tolerated. A single dose of 910 mg/m2 has been successfully administered to one patient. The multiple dose MTD is at an early stage with patients currently receiving 170 mg/m2 four times a week. Among the toxicities noted in both trials are hypotension, hypertension, emesis and somnolence. In addition, in the multiple dose trial there have been three patients who have had allergic reactions including one which was life-threatening. Phase II studies are planned and will begin when the maximum tolerated dose is established from each Phase I trial.
Assuntos
Amifostina/uso terapêutico , Neoplasias/radioterapia , Compostos Organotiofosforados/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Radioterapia/efeitos adversos , Dosagem RadioterapêuticaRESUMO
PURPOSE: To assess the impact of young age on outcome in women with early stage breast cancer undergoing conservative surgery and radiation. METHODS AND MATERIALS: Between 1981 and 1991, 980 patients with Stage I and II breast cancer underwent excisional biopsy, axillary dissection, and radiation. The median follow-up was 4.6 years, with a range of 1 month to 11 years. The patients were divided into three groups, based on age at the time of diagnosis: (a) age < or = 35 years--64 patients, (b) age 36-50 years--363 patients, and (c) age > 50 years--553 patients. The comparability of the groups was assessed in terms of clinical factors (tumor size and race), histopathologic factors (histologic subtype, final resection margin, estrogen and progesterone receptor status, pathologic nodal status), and treatment related factors (reexcision, median total dose to the primary, region(s) treated with radiation, and the use of adjuvant systemic chemotherapy and/or tamoxifen). Outcome was evaluated for overall, relapse-free, and cause-specific survival and patterns of first failure (breast, regional nodes, and distant metastasis). RESULTS: There were no significant differences among the three groups in terms of race, clinical tumor size, pathology of the primary tumor, pathologic nodal status, final margin of resection, progesterone receptor status, median total dose to the primary tumor, or the regions treated. However, younger women were significantly more likely to have estrogen receptor negative tumors, undergo reexcision, and receive adjuvant systemic chemotherapy without tamoxifen. Younger women were found to have a statistically significantly decreased 8-year actuarial relapse-free survival (53% vs. 67% vs. 74%, p = 0.009), cause-specific survival (73% vs. 84% vs. 90%, p = 0.02), freedom from distant metastasis (76% vs. 75% vs. 83%, p = 0.02), and a significantly increased risk of breast recurrence (24% vs. 14% vs. 12%, p = 0.001), and regional node recurrence (7% vs. 1% vs. 1%, p = 0.0002). The patients were further divided on the basis of their pathologic nodal status. There were no statistically significant differences among the three age groups for axillary node-positive patients for overall survival (75% vs. 80% vs. 74%), relapse-free survival (73% vs. 73% vs. 62%), cause-specific survival (76% vs. 85% vs. 80%), and freedom from distant metastasis (75% vs. 75% vs. 72%), or breast recurrence (0% vs. 9% vs. 6%). The findings were identical when the analysis was restricted to node-positive patients who received chemotherapy. However, for axillary node-negative women, young age was associated with a statistically significant decreased overall survival (71% vs. 83% vs. 92%), relapse-free survival (51% vs. 65% vs. 76%), cause-specific survival (71% vs. 86% vs. 93%), freedom from distant metastasis (77% vs. 76% vs. 88%), and a statistically significant increased risk of breast recurrence (40% vs. 16% vs. 13%), and regional node recurrence (3% vs. 1% vs. 0%). The risk of a breast recurrence in axillary node-negative young women was decreased by the addition of adjuvant systemic chemotherapy but not by the use of reexcision. CONCLUSIONS: The present analysis demonstrates that young women with early stage breast cancer do significantly worse when compared to older women in terms of relapse-free survival, cause-specific survival, distant metastasis and breast and regional node recurrence. However, the adverse effect of young age on outcome appears to be limited to the node-negative patients. These findings suggest that node-negative early stage breast cancer in young women is a more aggressive disease, with an increased risk for all patterns of failure and a decreased survival.