RESUMO
Intestinal lymphangiectasia is a disease characterized by dilated intestinal lymphatics, protein-losing enteropathy, hypoalbuminemia, and edema. The immunologic status of 18 patients with intestinal lymphangiectasia was studied. Concentrations of IgG, IgA, and IgM were measured by immune precipitation and metabolism of these three immunoglobulins was studied using purified radioiodinated proteins. The serum concentration and total body pool of each immunoglobin were greatly reduced. The fraction of the intravascular protein pool catabolized per day was increased to 34% for IgG, 59% for IgA, and 66% for IgM; these are in contrast with control values of 7%, 28%, and 17%, respectively. Synthetic rates of the immunoglobulins were normal or slightly increased. Primary circulating antibody response was tested in five patients with Vi and tularemia antigens. Titers elicited in patients with the Vi antigen were significantly lower than those seen in a control group, whereas no difference was seen between patient and control responses to the tularemia antigen. Lymphocytopenia was noted in patients with intestinal lymphangiectasia. The mean circulating lymphocyte count was 710 +/- 340/mm(3) in contrast to 2500 +/- 600/mm(3) in controls. Cellular hypersensitivity was studied with skin tests and skin grafts. 91% of normal individuals reacted to at least one of the four skin test antigens: purified protein derivative, mumps, Trichophyton, and Candida albicans; in contrast, only 17% of patients with intestinal lymphangiectasia had a positive reaction. Each of three patients tested with dinitrochlorobenzene had a negative reaction. Finally, all four patients who received skin homografts have retained these grafts for at least 12 months. The immunological disorders in patients with intestinal lymphangiectasia appear to result from loss of immunoglobulins and lymphocytes into the gastrointestinal tract secondary to disorders of lymphatic channels. Lymphocyte depletion then leads to skin anergy and impaired homograft rejection.
Assuntos
Formação de Anticorpos , Enteropatias Perdedoras de Proteínas/imunologia , Imunologia de Transplantes , gama-Globulinas/metabolismo , Adolescente , Adulto , Agamaglobulinemia/complicações , Contagem de Células Sanguíneas , Criança , Feminino , Humanos , Lactente , Isótopos de Iodo , Linfócitos , Masculino , Pessoa de Meia-Idade , Transplante de Pele , gama-Globulinas/análiseRESUMO
BACKGROUND: Despite some evidence that age does not meaningfully influence the efficacy or toxicity of cancer treatment, older patients tend to receive less comprehensive cancer therapies. PURPOSE: We conducted a population-based study to evaluate the selection of cancer treatment among the elderly. METHODS: Between September 1 and November 30, 1990, we interviewed by telephone a sample of 628 female Wisconsin residents recently diagnosed with breast (507) or colorectal (121) cancer. The women, aged 20-74 at the time of diagnosis, were identified through Wisconsin's statewide tumor registry. The approximately 30-minute long telephone interview, part of a larger study of cancer etiology, included questions on treatment history, physician specialty, and reasons for the selection of specific therapies. Analyses compared the proportion of subjects with various treatment characteristics according to age (< 65 and > or = 65 years). In evaluating the effect of age on selected therapies, we adjusted summary proportions for stage of disease using the indirect method. The Mantel-Haenszel chi square statistic was used to evaluate statistical significance of the differences in proportions. RESULTS: After adjusting for stage of disease at diagnosis, substantial variation was observed in cancer treatment according to age for both breast and colorectal cancer. Older women (> or = 65 years) with breast cancer were less likely than younger women (< 65 years) to have received conservative surgery, radiation, and adjuvant therapy. Older women were, in fact, more likely than younger women to accept mastectomy (P = .03). Consultation with a medical or radiation oncologist was less common among older than younger patients (57% versus 73%). Older women were also less likely to have alternative therapies presented to them (19% versus 31%). While older patients were less likely to have been offered adjuvant treatments, like chemotherapy (P < .01), they were also more likely than younger women to reject these treatments when offered (P = .01). These differences were observed in both breast and colorectal cancer patients. Regardless of age, the most common reasons for not selecting treatments were physicians' recommendations and the desire for more comprehensive treatment. Concern about side effects, however, was more frequently reported by older women (P = .07). CONCLUSION AND IMPLICATION: Patients' ages influence the choice of treatment. Physicians offer older women with cancer different treatments from those offered to younger women and are less likely to recommend specialist consultation. Physicians' advice and description of toxicity may influence patients' selection of treatment. However, older patients' concerns about the consequences of cancer treatment may also influence treatment choice.
Assuntos
Neoplasias da Mama/terapia , Neoplasias Colorretais/terapia , Revelação , Seleção de Pacientes , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Encaminhamento e Consulta , Medição de Risco , Suspensão de TratamentoRESUMO
A method was developed for the in vitro induction by 12-O-tetradecanoylphorbol-13-acetate (TPA) of ornithine decarboxylase (ODC) activity in human skin punch biopsy samples. Addition of TPA to 1 ml serum-free minimum essential medium containing a single 3-mm human skin punch biopsy sample obtained from a surgical specimen resulted in an induction of ODC activity with a peak activity at 5 hours after TPA addition. In vitro induction of human epidermal ODC activity was dependent on the TPA concentration in the medium; about a twofold increase in ODC activity was observed 6 hours after the addition of 0.1 microM TPA, and about a fivefold increase in ODC activity was observed with 1 microM TPA. TPA also caused about a fivefold to sixfold increase in ODC activity in 3-mm skin punch biopsy samples from healthy volunteers. Human skin punch biopsy samples remained responsive to TPA induction of ODC activity even when stored in serum-free medium at 4 degrees C for 24 hours. A similar degree of induction of ODC activity by TPA was observed whether whole unfractionated human epidermis or a soluble epidermal extract was used for ODC assays. Increased ODC activity was the result of the increase in enzymatically active ODC protein, quantitated by a [3H]difluoromethylornithine-binding assay. Thus human skin, like mouse skin, is responsive to TPA for ODC induction.
Assuntos
Carcinógenos/farmacologia , Ornitina Descarboxilase/biossíntese , Forbóis/farmacologia , Pele/enzimologia , Acetato de Tetradecanoilforbol/farmacologia , Amputação Cirúrgica , Biópsia , Indução Enzimática/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Epiderme/enzimologia , Humanos , Pele/efeitos dos fármacosRESUMO
We observed major responses in two patients with adenocarcinoma of the lung who had received a combination of interferon (IFN)-beta and IFN-gamma, immediately followed by chemotherapy. To verify these observations, we initiated a prospective randomized phase II-III trial of etoposide and cisplatin, with or without IFN-beta and IFN-gamma, in patients with inoperable non-small cell lung cancer. Thirty-seven patients were randomized to receive either two cycles of chemotherapy or 6 weeks of IFN-beta plus IFN-gamma followed by two cycles of chemotherapy. Chemotherapy consisted of 60 mg of cisplatin/m2 on day 1 and 120 mg of etoposide/m2 on days 4, 6, and 8, repeated every 21 days. Patients who were randomized to the IFN plus chemotherapy arm received 200 micrograms of IFN-gamma and 30 x 10(6) U of IFN-beta three times per week for 6 weeks, followed by two cycles of chemotherapy. Three of 18 (17%) eligible patients in the chemotherapy arm and two of 18 (11%) patients in the combination arm had partial responses. All responses occurred while patients were receiving chemotherapy. Median survival was 190 days for the chemotherapy arm and 246 days in the combined modality arm, as estimated from Kaplan-Meier curves (P = .35). We observed no significant difference in subjective toxic effects between the two arms. We observed more hematologic toxicity during chemotherapy on the combined modality arm (P = .02). We conclude that pretreatment with IFN-beta and IFN-gamma does not enhance the efficacy of etoposide and cisplatin in this disease. Although the combined modality arm is relatively well tolerated, it does result in more chemotherapy-associated toxic effects. This study also exemplifies a hybrid phase II-III trial design, which is useful in allowing phase II results to be quickly incorporated into a phase III trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Esquema de Medicação , Avaliação de Medicamentos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Humanos , Interferon Tipo I/administração & dosagem , Interferon gama/administração & dosagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
BACKGROUND: alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice. PURPOSE: A randomized phase I study of DFMO was conducted to determine the lowest daily oral dose that can achieve at least 50% inhibition of ODC activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human skin, with minimal clinical toxicity (grade 1 or lower; Eastern Cooperative Oncology Group [ECOG]). METHODS: Cancer patients entered in steps 1 and 2 of the study had been treated and had no clinical evidence of cancer. In step 1, 13 patients received 0.125, 0.25, 0.5, or 0.75 g/m2 DFMO four times a day. In step 2, 13 patients received 0.125 or 0.25 g/m2 four times a day or 0.5 or 1.0 g/m2 every day. The 26 patients treated in steps 1 and 2 (range, < 1-6 months) had colon, prostate, or bladder cancer. In step 3, six cancer-free subjects at risk for colorectal cancer received 0.5 g/m2 every day for 5-12 months. To evaluate the effectiveness of DFMO in reducing TPA-induced ODC activity, we calculated the percent change from pretreatment ODC levels in skin biopsy specimens and the percentage of subjects with at least a 50% reduction in ODC levels. RESULTS: In step 1 of the study, treatment-limiting audiotoxicity was observed at the three highest doses. Because the only dose with no major toxic effects in step 2 was 0.5 g/m2 every day, that dose was administered in step 3, with no major toxic effects. Seven subjects treated with 0.5 g/m2 every day had pretreatment ODC levels in the normal range; five averaged a reduction in ODC activity of at least 50%. DFMO had linear pharmacokinetics over the entire dose range. When 0.5 g/m2 was given every day, the peak plasma concentration was 47.1 +/- 5.1 microM at 3-4 hours (monthly mean +/- SE, 14.5 +/- 5.2 microM); half-life was 3.5 hours; and area under the curve for plasma concentration x time for a single dose of DFMO was 311 +/- 39 microM x hour. CONCLUSIONS: These data support phase II chemoprevention studies with DFMO given at a dose of 0.5 g/m2 every day. IMPLICATIONS: Studies investigating prevention of cancers with DFMO are under consideration.
Assuntos
Carcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Eflornitina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Eflornitina/farmacocinética , Indução Enzimática/efeitos dos fármacos , Feminino , Humanos , Masculino , Ornitina Descarboxilase/metabolismo , Pele/enzimologia , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
We conducted a 2-year, randomized, double-blind, placebo-controlled toxicity trial of therapy with tamoxifen (10 mg twice a day) in 140 postmenopausal women with a history of breast cancer and histologically negative axillary lymph nodes. These women had been treated with surgery with or without radiotherapy. At a 3-month evaluation, tamoxifen-treated women showed a significant decrease in fasting plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, which persisted at 6- and 12-month evaluations. During the first 12 months, plasma triglyceride levels increased; small but significant decreases in high-density lipoprotein cholesterol (HDL) were observed in tamoxifen-treated women, but ratios of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol changed favorably. While data relating lipid/lipoprotein profiles and cardiovascular disease are limited in women, current evidence suggests that total cholesterol and possibly low-density lipoprotein cholesterol are risk factors. We conclude that during the first 12 months of treatment, tamoxifen exerts a favorable effect on the lipid profile in postmenopausal women with early stage breast cancer.
Assuntos
Neoplasias da Mama/sangue , Lipídeos/sangue , Lipoproteínas/sangue , Menopausa/sangue , Tamoxifeno/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Colesterol/sangue , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Linfonodos/patologia , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/efeitos adversos , Triglicerídeos/sangueRESUMO
Basic biological principles in cancer biology can be learned from laboratory experiments as well as the clinic. The clinical investigator may be able to uncover cancer biology and clinical cures, an exciting possibility. Clinical trials can and should be designed to discover biological principles as well as to test one option of surgery or drug combination versus another. During the past 20 years, a variety of clinical research programs in patients with myeloma, chronic myelogenous leukemia, lymphoma, and breast cancer have led to the discovery of important biological principles. These include contributions leading to the origin of myeloid and lymphoid cells in the marrow, the discovery of immunoglobulin D myeloma, the development of effective combination chemotherapy in Hodgkin's disease, and the concept of adjuvant therapy in breast cancer. These studies also have led to improved or new therapy for these diseases. Future research and cancer cures will undoubtedly be facilitated by close collaboration between the clinical and the laboratory investigator.
Assuntos
Oncologia , Neoplasias/terapia , Animais , Humanos , Prognóstico , Sociedades Médicas , Sociedades CientíficasRESUMO
Laboratory research is often described as basic and clinical research, prognostic or empirical. In this address, the point is made that research may be clinical or laboratory. Good clinical research may give important biological answers. Breast cancer clinical trials are decribed in terms of their biological interpretation. A list of significant biological questions that need answering are presented.
Assuntos
Neoplasias/terapia , Adulto , Idoso , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Castração , Sobrevivência Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Feminino , Hormônios/uso terapêutico , Humanos , Metástase Linfática , Mastectomia/métodos , Menopausa , Pessoa de Meia-Idade , Metástase Neoplásica , Células Neoplásicas Circulantes , Remissão Espontânea , Projetos de PesquisaRESUMO
Because cancer is the number one cause of mortality in Taiwan, a governmental decision was made to develop an experiment in medical oncology education using a United States-style training program in medical oncology in three Taipei, Taiwan, university hospitals. In the past, trainees from developing countries came to the United States or other foreign countries to receive specialty training. In doing so, the training did not necessarily prepare the individuals with skills to treat the indigenous cancers, nor did they work with other related specialists or support staff such as nursing and pharmacy, so important to providing good cancer care. This program involved 13 fellows with significant laboratory experience working with American faculty on-site. The major benefits of this model for oncology training are that the trainees developed important interdisciplinary relationships with local staff at each of the hospitals; they were involved in the treatment of the major cancer diseases of Taiwan such as nasopharyngeal, hepatocellular, and cervical cancers as well as breast, lung, and colon cancers; and they completed a certification process involving written and oral tests by two senior American oncologist examiners. Oncology services have been established at each of the hospitals and most of the fellows have expressed an interest or made arrangements to come to the United States to get additional research experience.
Assuntos
Educação de Pós-Graduação em Medicina/organização & administração , Oncologia/educação , Avaliação Educacional , Docentes , TaiwanRESUMO
Extensive animal data have suggested that, in some systems, the induction of ornithine decarboxylase (ODC) is an essential, although not sufficient, aspect of tumor promotion and that compounds that inhibit ODC can inhibit tumor formation. Using fasting human volunteers, we report that human epidermal and dermal ODC are consistently induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in a manner similar to that seen in mouse skin. There is a marked intersubject variation in TPA-induced epidermal ODC activity levels. Orally administered compounds significantly inhibited TPA-caused human epidermal ODC induction. These data may be useful in the further development of drugs, doses, and dose schedules for use in human cancer chemoprevention studies.
Assuntos
Indometacina/farmacologia , Inibidores da Ornitina Descarboxilase , Pele/efeitos dos fármacos , Tretinoína/farmacologia , Adulto , Células Cultivadas , Indução Enzimática/efeitos dos fármacos , Feminino , Humanos , Isotretinoína , Masculino , Pele/enzimologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/prevenção & controle , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
PURPOSE: We studied oncologists' attitudes and behavior with regard to their participation in randomized clinical trials. METHODS: We surveyed the 1,737 physician members of the Eastern Cooperative Oncology Group (ECOG) using the Physician Orientation Profile (POP), a self-administered mailed questionnaire. A response rate of 86% was achieved (1,485 of 1,737); each physician's actual patient accrual was recorded. RESULTS: All respondents indicated that they had a systematic pattern of patient preselection for entry onto trials beyond the formal inclusion/exclusion trial criteria. Eighty-nine percent stated that improving patient quality of life rather than prolonging survival was more personally satisfying. Sixty-two percent did not enter a single patient during the 12-month period following the survey, while 10% entered 80% of all patients during that time. Physicians overestimated their accrual rate by a factor of 6. Eighty-three percent defined randomization and adherence to trial protocol as a serious challenge to their ability to make individualized treatment decisions. CONCLUSION: This study raises questions regarding the following: (1) the perceived generalizability of trial findings, (2) the role of end points other than survival for clinical trials, (3) the consequences of physician overestimation of patient accrual, and (4) the impact of randomized trials on the behavior of clinicians. Further investigation into these critical issues will provide meaningful recommendations to enhance the future design, implementation, and conduct of randomized clinical trials in cancer.
Assuntos
Oncologia , Estudos Multicêntricos como Assunto , Neoplasias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Atitude do Pessoal de Saúde , Canadá , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Estados UnidosRESUMO
After mastectomy, 265 postmenopausal patients with node-positive breast cancer were stratified according to pathologic nodal status and estrogen-receptor (ER) status and randomized to receive either 12 cycles of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP), or CMFP plus tamoxifen (CMFPT), or observation alone. Patients entered the study between March 1978 and July 1981. Cox regression analysis indicated that, compared to observation alone, chemotherapy (CMFP and CMFPT groups combined) led to a significant reduction in relapses by the end of the first year of study in every examined prognostic subgroup. However, after the first year the relapse-free survival curves of all treatment groups tended to merge, so that by three years 52% of the observation group and 51% of the chemotherapy groups remained disease free. Chemotherapy continued to show a significantly superior relapse-free survival rate for three years only in the subgroup of patients with ER-negative tumors (the subgroup with the largest relapse-free survival advantage at one year). The addition of tamoxifen produced no benefit or harm in any prognostic subcategory examined. ER status was prognostically important for predicting early relapse only in those patients not receiving chemotherapy, due to the greater effectiveness of this chemotherapy to prevent early relapse in the ER-negative subgroup. Treatment has had no early effect on survival. As breast cancer continues to recur even after ten or more years, later relapse patterns may alter these results.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Diabetes Mellitus Tipo 1/complicações , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Doenças Hematológicas/induzido quimicamente , Humanos , Metástase Linfática , Mastectomia , Menopausa , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Primárias Múltiplas/tratamento farmacológico , Obesidade/complicações , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prognóstico , Distribuição Aleatória , Receptores de Estrogênio/análise , Risco , Tamoxifeno/efeitos adversosRESUMO
Thirty-two women with advanced local regional breast carcinoma, including nine patients with histologically diagnosed inflammatory cancer, were entered on a prospective pilot study. They were treated aggressively with initial surgery, two courses of induction chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil, +/- prednisone, +/- tamoxifen (CMF [P] [T]), local-regional radiotherapy, and then maintenance chemotherapy with CMF(P) (T) alternating with doxorubicin, vincristine, +/- tamoxifen (AV[T]). The patients have been followed for 19-70 months from the time of mastectomy and their actuarial three-year survival is 65% with a median survival that has not yet been reached. Median disease-free survival (time to progression) is currently 29.5 months. Women whose gross disease could not be totally resected surgically had shorter disease-free survivals than those rendered surgically free of disease (p = 0.01). Clinically evident cardiotoxicity was seen in 25% of the patients and was felt to be primarily due to the combination of doxorubicin and radiation therapy. It was significantly more common (Plt less than 0.05) in patients with left chest irradiation (seven of 18 women) as opposed to those with right-sided irradiation (one of 14).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Cardiomegalia/induzido quimicamente , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Mastectomia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Projetos Piloto , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos ProspectivosRESUMO
This study addressed two major questions regarding therapeutic use of Adriamycin ([Adr] Adria Laboratories, Columbus, OH) in adult soft tissue sarcomas: the influence of dosing schedule and the value of adding imidazole carboxamide (DTIC) to Adr. Patients with objectively measurable metastatic soft tissue sarcomas were randomized to Adr 70 mg/m2 intravenously (IV) day 1 and every 3 weeks (94 patients); Adr 20 mg/m2 IV day 1, 2, and 3, and 15 mg/m2 IV day 8 and weekly thereafter (89 patients); and Adr 60 mg/m2 IV day 1 and DTIC 250 mg/m2 days 1 to 5, repeated every 3 weeks (92 patients). The regimens using Adr as a single agent resulted in an equivalent response frequency (18% and 16%) and survival (median, 8.0 and 8.4 months). DTIC significantly increased (P less than .02) the overall response frequency of Adr to 30%. However, DTIC did not influence survival (median, 8.0 months) or increase the number of complete responses. The toxicities of the two single-agent regimens differed: Adr weekly resulted in more stomatitis (P = .09) and less hematologic toxicity (P less than .05). DTIC resulted in substantially increased toxicity, primarily gastrointestinal (P less than .002); overall, 98% of patients receiving Adr-DTIC experienced moderate or worse toxicity. To decrease the potential for error in interpretation of treatment results, histopathological confirmation of diagnosis was undertaken by a panel of reference pathologists; pathology slides were submitted on 97% of entered patients. The on-study clinical diagnosis was affirmed in 199 of 316 patients (63%) with a final review. In 23% of patients, the panel agreed with the diagnosis of soft tissue sarcoma, but not with the type. In 14%, the panel concluded that a diagnosis of mesenchymal malignancy could not be affirmed. Final treatment results were based on the 275 pathologically confirmed, eligible patients. The most common histological subtype entered was leiomyosarcoma (99 patients). The response to Adr-DTIC of this subtype was higher (44%) than that of any other subtype. However, this difference alone was not responsible for the overall superiority of the combination. This confirmed that the combination of DTIC plus Adr adds to the response rate of Adr alone in soft tissue sarcomas. Whether the increased response frequency, without an impact on survival, is worth the significantly greater toxicity remains a subjective judgement that must be made within the context of the individual patient.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Cooperação do Paciente , Distribuição Aleatória , Sarcoma/patologiaRESUMO
The Eastern Cooperative Oncology Group (ECOG) trial of adjuvant cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen (CMFPT) for 1 year compared with observation alone in 265 postmenopausal patients with node-positive breast cancer is reported with 74 months median follow-up. Overall relapse-free survival tended to favor CMFPT (P = .08), but no survival differences existed between any treatment group. The addition of tamoxifen to CMFP led to slightly (but not significantly) better relapse-free status in all subgroups analyzed. Subgroup analysis based on stratification variables showed significant benefit from CMFP (+/- T) only in estrogen receptor (ER)-negative patients with respect to disease-free status (P = .0003), but not survival (P = .54). Relapse-free status was actually worse for CMFP-treated patients with ER-positive tumors, but not significantly so (P = .15). By multivariate analysis other significant risk factors for relapse-free status were primary tumor size, number of nodes pathologically involved, and the number of nodes examined. ER status was prognostic only for the observation group with the benefit from chemotherapy on ER-negative patients obliterating this difference in treated patients. Survival was affected by the number of involved nodes, tumor size, presence of tumor necrosis, and patient obesity. Analysis of toxicity showed elevation of liver enzymes during the first year to be more common in the observation group compared with those patients receiving adjuvant treatment and to be associated with early recurrence. Toxicity from adjuvant treatment persisted beyond termination of therapy in 53% of patients, but was usually mild and self-limited. We conclude CMFPT offers relapse-free survival benefit in ER-negative patients, but the value of chemotherapy in ER-positive postmenopausal, node-positive patients must be questioned.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Menopausa , Neoplasias da Mama/mortalidade , Ensaios Clínicos como Assunto , Ciclofosfamida/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Distribuição Aleatória , Receptores de Estrogênio/efeitos dos fármacos , Tamoxifeno/administração & dosagemRESUMO
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
The development of chemotherapy for patients with the major cancers progressed from the initial success attained in the treatment of acute leukemias and choriocarcinoma. Many of the principles of therapy were based on the concepts developed in the experimental laboratories and early clinical studies done at the NIH Clinical Center and other centers around the country. The purpose of this review is to describe some of the early advances in cancer therapy and show how many are based on the efforts of Dr. Emil J Freireich. Over his career, Dr. Freireich has published more than 500 papers and worked on more than 70 different drugs and combinations. The principles defined by Dr. Freireich, namely, the use of intermittent intensive chemotherapy to induce complete remissions (CRs), intensification of therapy in remission, and the use of unmaintained remissions to assess cure, have been important in developing curative chemotherapy programs in patients with acute leukemias. These same principles were applied to combination therapy of Hodgkin's disease as the nitrogen mustard, vincristine, procarbazine, and prednisone combination was developed. This led to the high CR and cure rate for this disease. The treatment of metastatic breast cancer does not produce a high proportion of CRs, and cures of metastatic disease are unlikely with chemotherapy alone. But adjuvant chemotherapy after surgery has resulted in a significant reduction in cancer mortality. Many challenges remain in increasing the cure rate for the major solid tumors. New avenues of controlling cell growth and metastases need to be explored. One approach that is exploitable is the use of drugs or nutrients to prevent cancer. Laboratory approaches are now becoming a clinical reality.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Ensaios Clínicos como Assunto , História do Século XX , Humanos , Oncologia/história , Estados UnidosRESUMO
The purpose of this study was to assess the bioavailability of two oral preparations of difluoromethylornithine (DFMO). The current preparation of DFMO is a liquid with a concentration of 0.2 gram/ml that must be drawn up into a syringe and dispensed into a small medicine glass. This form of DFMO causes wastage of the medication. The liquid form also makes compliance and blinding difficult. Recently, a new coated tablet preparation has become available from Ilex Oncology Services (San Antonio, TX). The coated tablets are 0.25 gram and are scored. The tablet form should increase compliance by making it much easier for the subject to take the medication. This report compares the bioavailability of both preparations with the goal of demonstrating equivalence of the preparations. Ten normal subjects entered the cross-over study in which the order in which they would receive the liquid or tablet preparation of DFMO was randomized. The study was designed with the objective of establishing the bioequivalence of a tablet preparation of DFMO at daily dose 0.5 gram/m2 and a liquid preparation of DFMO at the same daily dose. The mean area under the time-by-concentration curves (microM x hours) for the liquid and tablet preparations was 368.2 and 370.4, respectively. The peak concentrations for the liquid and tablet preparations were 47.3 and 48.2 microM, respectively. No statistically significant differences were seen in these parameters, in time to peak concentration, or in serum half-life.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Eflornitina/administração & dosagem , Eflornitina/farmacocinética , Administração Oral , Adulto , Antineoplásicos/toxicidade , Área Sob a Curva , Estudos Cross-Over , Relação Dose-Resposta a Droga , Eflornitina/toxicidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos , Fatores de TempoRESUMO
A syndrome, including microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and renal insufficiency, has been recognized to occur as a complication of antineoplastic therapy with mitomycin. The clinical presentation can vary from a chronic course with mild anemia and slowly progressive renal dysfunction to a fulminant course with severe anemia, rapid deterioration of renal function, and death. The optimal treatment of the mitomycin-associated MAHA syndrome is unknown. Therapy with steroids, antiplatelet agents, and heparin sodium has failed to reverse the MAHA. Plasmapheresis has improved the MAHA in a few patients without reversing the renal failure. We treated two patients who had MAHA and renal dysfunction during chemotherapy that included mitomycin; the MAHA and hypertension both objectively improved after treatment that included vincristine sulfate.
Assuntos
Anemia Hemolítica/induzido quimicamente , Mitomicinas/efeitos adversos , Vincristina/uso terapêutico , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Adenocarcinoma/tratamento farmacológico , Adulto , Anemia Hemolítica/complicações , Anemia Hemolítica/tratamento farmacológico , Anemia Hemolítica/fisiopatologia , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Metástase Neoplásica , Síndrome , Trombocitopenia/tratamento farmacológicoRESUMO
An enhancing interaction of a human serum factor with other sources of colony stimulating activity (CSA) is described. Using a mouse colony forming cell assay, the enhancing effect of human serum was observed with suboptimal doses of colony stimulating material from monocytic cell feeder layers, supernatant from peripheral monocytic cells, and L cell supernatant. The enhancing factor is heat stable, is not dialyzable and is not extractable by ether. The enhancing phenomenon does not require the presence of viable cells in the feeder layers. The observation of enhancing interaction makes interpretation of all data from CSA stimulation experiments more complex than previously appreciated.