Dose-related pharmacologic effects of high dose ara-C and its use in combination with asparaginase for the treatment of patients with acute non-lymphocytic leukemia.
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Acute Disease↗
Biomedical subjects
J J Stuart
Publications and source records attributed to J J Stuart.
Combination chemotherapy (5-fluorouracil, methyl-CCNU, mitomycin C) versus 5-fluorouracil alone for advanced previously untreated colorectal carcinoma. A phase III study of the Piedmont Oncology Association.
One-hundred thirty eligible patients with advanced colorectal carcinoma who had received no prior chemotherapy were randomized to either methyl-CCNU, 70 mg/m2 orally every 6 weeks on day 1, mitomycin C, 10 mg/m2 intravenously every 6 weeks on day 1, and 5-fluorouracil (5-FU), 400 mg/m2 intravenously weekly--(MMF)--or 5-FU, 600 mg/m2 intravenously weekly (5-FU). One hundred twenty-six patients are evaluable for response. Of 62 patients treated with MMF, one (2%) achieved complete remission, and three (5%) attained partial remission. Of 64 patients treated with 5-FU, two (3%) achieved complete remission, and eight (13%) attained partial remission. The median survival for patients receiving MMF was 9.5 months compared with 10.3 months for patients receiving 5-FU. The survival distributions for the two regimens were not significantly different, either unadjusted or adjusted for pretreatment characteristics. Performance status and lactic dehydrogenase (LDH) were both significantly associated with survival. Patients with liver metastases only and normal liver function tests had a median survival of 19.8 months and a 40% response rate. This randomized phase III trial did not show any therapeutic advantage for MMF compared to 5-FU therapy alone in advanced colorectal cancer. In addition, hematologic toxicity was significantly greater with the combination (MMF) regimen.
Adolescent↗
A randomized trial of adjuvant chemotherapy and immunotherapy in Stage I and Stage II cutaneous melanoma. An interim report.
Seventy patients with Stage I and II malignant melanoma were randomized to treatment with either intravenous dacarbazine alone or intravenous dacarbazine plus intradermal injection of the methanol-extracted residue of bacillus Calmette-Guerin (BCG). Analysis of treatment failed to reveal a statistically significant difference between these two forms of treatment in Stage I and II patients. It is possible that chemoimmunotherapy may increase survival in Stage II patients, but this possibility should be interpreted with caution.
Adult↗
The incidence of thrombotic and hemorrhagic disorders in association with extreme thrombocytosis: an analysis of 129 cases.
We have presented a retrospective study of 129 patients with platelet counts of 1,000 X 10(9)/L or more--72 with myeloproliferative disorders (MPD), and 57 with reactive thrombocytosis (RT)--in an effort to determine the incidence of thrombohemorrhagic complications. Thrombotic disorders occurred with approximately equal frequency in the two groups, being found in three patients (4%) with MPD and three (5%) with RT when the platelet count was over 1,000 X 10(9)/L and in 11% of the patients in each group when the platelet count was less than 1,000 X 10(9)/L. In contrast, bleeding manifestations were more common in MPD, where 36% of patients were affected on one or more occasions versus only 4% of those with RT. However, bleeding was generally not severe, with only six patients requiring transfusions, and three of these patients had been receiving aspirin or corticosteroids when they developed severe gastrointestinal bleeding.
Aged↗
A phase I trial of recombinant leukocyte alpha 2 interferon in patients with advanced malignancy.
Seventeen patients with advanced, previously treated malignancies were entered into a phase I trial utilizing recombinant DNA produced alpha 2 leukocyte interferon (rIFN-alpha 2). Sixteen patients were evaluable. Patients were to receive rIFN-alpha 2 by either the I.V. or I.M. route for 35 consecutive days. The dosage was identical by both routes, and patients were escalated from 3 X 10(6) to 10 X 10(6) to 30 X 10(6) to 50 X 10(6) and to 100 X 10(6) I.U. every 7 days. No patient was able to tolerate the consecutive treatment protocol as planned. Dose-limiting toxicity was a flu-like syndrome in 10 patients and was usually associated with a fall in performance status. Confusion resulted in study withdrawal for five patients, four receiving rIFN-alpha 2 by the I.M. route. Hematologic and liver function abnormalities were common, usually transient, and not associated with clinical sequelae. One patient with non-Hodgkin's lymphoma showed substantial improvement; otherwise, all had stable or progressive disease. Pharmacologic studies indicated substantial serum levels at doses greater than or equal to 10 X 10(6) I.U. regardless of route. No consistent changes in NK activity, lymphocyte subpopulations, or immunoglobulin levels were noted, and no patient developed antibodies to rIFN-alpha 2. The dose and schedule used here indicate that high levels of serum rIFN-alpha 2 activity are obtainable by either the I.M. or I.V. route. Intermittent rather than daily dosage is more likely to be better tolerated and should be considered for phase II trials.
Adult↗
Single agent vincristine by infusion in refractory multiple myeloma.
A phase 2 trial of vincristine infusion was conducted in a group of 21 patients with refractory multiple myeloma. Patients were generally heavily pretreated with radiotherapy and chemotherapy. Vincristine was given intravenously (IV) as a 0.5 mg bolus and followed immediately by infusion of 0.25 to 0.50 mg/m2/d for 5 days. Courses were repeated every 3 weeks in the absence of disease progression or prohibitive toxicity. Objective responses (partial) were noted in two patients (10%), both of whom were administered 0.5 mg/m2/d infusions. Response durations were brief (2.2 and 1.2 months). Toxicity consisted of neurotoxicity and myelosuppression. In addition to the occurrence of paresthesias and myalgias, ileus (two cases) and moderately severe loss of motor function (two cases) were observed. The mean lowest WBC count following treatment was 2.67 X 10(3)/microL v 3.96 X 10(3)/microL pretreatment (P = .008). The mean lowest platelet count was 75.0 X 10(3)/microL v 106.8 X 10(3)/microL pretreatment (P = .008). Vincristine infusion appears to have limited activity in the treatment of refractory multiple myeloma. Additionally, response durations were short lived and toxicity, both neurologic and hematologic, was appreciable.
Adult↗
Megestrol acetate v tamoxifen in advanced breast cancer: a phase III trial of the Piedmont Oncology Association (POA).
One hundred twenty-four patients with recurrent or metastatic breast cancer were randomized to receive megestrol acetate 40 mg orally, four times daily, or tamoxifen 10 mg orally twice daily. If therapy failed patients were crossed over to the alternate treatment. Eligibility required that either the estrogen or progesterone receptor be positive or that both values be unknown, and that patients be at least 2 years postspontaneous menopause or over 50 years of age. Pretreatment characteristics were similar for both groups. Three patients had had previous hormonal therapy while one third had had chemotherapy. Objective response for evaluable patients based on strict UICC criteria was 29% with megestrol acetate and 31% with tamoxifen. Responses in patients with bone and soft tissue disease were similar for both regimens; however, 7 of 19 (37%) patients with visceral disease responded to tamoxifen but none of 18 (0%) responded to megestrol acetate. Response did not correlate with amount of estrogen or progesterone receptor. Unadjusted analysis of time to progression and survival showed no significant differences between regimens. With adjustment for pretreatment characteristics, patients on tamoxifen had a statistically significant prolongation of both of these parameters. Crossover data show 3 of 24 patients responding to tamoxifen after failure on megestrol acetate and 1 of 24 responding to megestrol acetate after failure on tamoxifen. However, crossover data should be viewed cautiously, as patients who are currently responding to initial treatment are those who would be most likely to respond to crossover therapy.
Aged↗
Sequential high-dose ara-C and asparaginase in the therapy of previously treated and untreated patients with acute leukemia.
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Aging↗
Interferon and doxorubicin in renal cell carcinoma.
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Adenocarcinoma↗
Treatment of advanced non-Hodgkin's lymphoma with vincristine infusion.
Twenty-five patients with a variety of histologic types of advanced non-Hodgkin's lymphoma refractory to previous chemotherapy were entered into a trial of vincristine infusion. Patients received 5-day courses of vincristine 0.25 mg/m2/day by continuous intravenous infusion after an initial 0.5 mg intravenous bolus injection. Courses were repeated every 3 weeks. Objective responses were observed in nine patients (36%), all of whom had previously received vincristine given by conventional bolus injection. A complete response occurred in a patient with diffuse mixed histiocytic lymphocytic lymphoma, and partial responses were observed in eight patients with the following histologic types: diffuse poorly differentiated lymphocytic (4); nodular poorly differentiated lymphocytic (2); diffuse mixed histiocytic lymphocytic (1); and diffuse histiocytic (1). Duration of response lasted from 1.2 to 16.2 months (mean, 4.4 months). The principal complication of therapy was mild-to-moderate neurotoxicity; this occurred in 12 patients (48%) who received a total of 54 courses of vincristine infusion. Hematologic toxicity was minimal and nausea/vomiting did not occur. Vincristine infusion may afford palliation for patients with advanced non-Hodgkin's lymphomas who have become refractory to standard chemotherapeutic regimens even if they have received prior vincristine by conventional bolus injection. These data suggest the possibility of enhancing the therapeutic efficacy of vincristine in the treatment of non-Hodgkin's lymphoma by use of an infusion technique.
Adult↗
Bone marrow evaluation in small cell lung cancer.
The records of 87 patients with small cell lung cancer were reviewed. Patients were clinically staged with bone marrow aspirate and biopsy as well as radionuclide scans of bone, liver, and brain. Extrathoracic spread was noted in 54% (47/87) and limited disease in 46% (40/87). The bone marrow evaluation was positive in 13/62 patients (21%) and seven of these thirteen patients had normal bone scans (54%). Of these seven patients, five had no other evidence of distant metastases and their survival was 7-10 months, considerably shorter than patients found to have limited disease. Bone marrow examination appears to complement radionuclide scanning in the initial staging of patients with small cell carcinoma of the lung and provides important prognostic information.
Bone Marrow Examination↗
A phase II study of dibromodulcitol (DBD) in stage IV melanoma.
Twenty-four patients were evaluated in a non-randomized study to assess the effectiveness of dibromodulcitol (DBD) in Stage IV melanoma. Patients received 100 mg/m2 of DBD orally for 35 days. The dose was escalated to 130 mg/m2 and then to 160 mg/m2 if no significant hematologic toxicity occurred. There were no objective responses, including six patients who had had no prior chemotherapy. Five patients (21%) remained stable. Median survival was 151 days. Survival favored females, nonvisceral involvement pretherapy, and patients with a disease-free interval (DFI) of greater than 1 year. None of these advantages was statistically significant. Toxicity was predominantly hematologic, but nausea, vomiting, shortness of breath, and diarrhea were also seen. Oral DBD, using this dose and schedule, does not appear efficacious in advanced disseminated melanoma.
Drug Administration Schedule↗
Subacute bacterial endocarditis causing disseminated intravascular coagulation: resolution after valve replacement.
The following report describes a case of culture-negative subacute bacterial endocarditis complicated by disseminated intravascular coagulation which failed to respond to therapy with antibiotics and heparin. The coagulopathy resolved within 24 hours after the affected heart valves were replaced with prosthetic valves.
Disseminated Intravascular Coagulation↗
Treatment of poor risk acute leukemia with sequential high-dose ARA-C and asparaginase.
Resistance of leukemia cells to cytosine arabinoside (ARA-C) may be due to any one or combination of biochemical processes, which in certain instances may be substantially reversed by an appropriate increase in ARA-C dosage. Based on these and other laboratory observations indicating pharmacologic synergy between sequential high-dose ARA-C and asparaginase (HiDAC----ASNase), a therapeutic program was developed for the treatment of patients with acute nonlymphocytic leukemia (ANLL) refractory to conventional doses of ARA-C, as well as patients with high risk ANLL and advanced acute lymphocytic leukemia (ALL). Treatment consisted of 3-hr intravenous infusions of 3 g/sq m of ARA-C given at 12-hr intervals for 4 doses, followed by 6,000 IU/sq m ASNase given i.m. at hour 42. The same schedule was repeated on day 8. In 32 induction attempts, only 4 patients proved to be truly refractory, i.e., failed to achieve substantial leukemia cell cytoreduction. Complete remissions were achieved with HiDAC---- ASNase in 9 of 13 patients with refractory ANLL, 6 of 9 patients with antecedent hematologic disorders, and 3 of 10 patients with advanced ALL. These include 9 of 14 patients who had either failed induction or who had relapsed on active ARA-C therapy and 6 of 8 patients who had had no prior exposure to ARA-C. The median duration of unmaintained remission in ANLL was 5 mo. In a patient with central nervous system (CNS) leukemia, there was clearance of cerebral spinal fluid (CSF) blasts without intrathecal therapy, suggesting a role for HiDAC in CNS prophylaxis. In general, toxicity was tolerable and reversible. These data suggest that HiDAC----ASNase is an exceptionally effective and well tolerated regimen in leukemic patients with antecedent hematologic disorders and in those refractory to conventional doses of ARA-C.
Acute Disease↗
Informed consent: patient information forms in chemotherapy trials.
Documentation of informed consent by patients entering clinical trials is an ethical and legal necessity. Federal regulations and judicial opinions have led to increasingly lengthy, detailed "consent" forms, yet published studies demonstrate that patients remain confused about the nature and anticipated consequences of study entry. It has been suggested that more detail may even alarm or further confuse patients. Seventy-five women undergoing chemotherapy for advanced breast cancer participated in this study which assessed patient preference for long-, medium-, or short-form length, and whether form length preference correlated with patient characteristics or indicators of patient autonomy in decision-making or physician dependency. Patient preferences for information were not predicted by the patient autonomy or physician dependency scores or by age, marital status, or level of education. The majority of patients expressed a preference for more detailed information about their treatment, yet a majority of patients given detailed forms answered questions basic to the study design incorrectly, irrespective of educational level. The increased detail included in the long forms was not reported to increase stress compared to the short forms. Patient information forms are a principal tool for informing patients for consent but if they are to perform their desired function they must be designed more carefully and evaluated more thoroughly than in the past.
Age Factors↗
Vincristine, doxorubicin and mitomycin (VAM) in patients with advanced breast cancer previously treated with cyclophosphamide, methotrexate and fluorouracil (CMF). A clinical trial of the Piedmont Oncology Association (POA).
Thirty-six evaluable patients with advanced breast cancer who had failed prior CMF therapy [15 (42%) as adjuvant treatment and 21 (58%) for advanced disease] were treated with a combination of vincristine, doxorubicin, and mitomycin (VAM). There was one CR and 10 PR, giving a response rate of 31% (P, 95% confidence interval, 15%-47%). Response was not significantly related to age, performance status, disease-free interval, dominant site of disease, number of sites of disease, or estrogen receptor status. The median duration of response was 5 months for patients attaining CR or PR and 4.6 months for patients with stable disease. The median survival for patients with CR or PR of 7.9 months was not better than for those with stable disease (8.0 months), but both groups had significantly longer survival than those with initial progression. Patients who received VAM after failing adjuvant CMF had a 53% response rate (8 of 15), as against a 14% response rate (3 of 21) in those failing CMF for advanced disease (P less than 0.05). In spite of this difference, the survival distributions for these two groups were not significantly different. Myelosuppression was moderate and no cardiac toxicity was seen. The addition of mitomycin to vincristine and doxorubicin in previously treated patients does not appear to improve the results obtained with vincristine and doxorubicin alone.
Adult↗
Lack of potentiation of vincristine-induced neurotoxicity by VP-16-213.
Due to a recent alarming report suggesting that the severe neurotoxicity observed following treatment with a multiagent chemotherapy regimen might be due to the interaction of vincristine and VP-16-213, the neurologic toxicity data from a randomized trial conducted by the Bowman Gray School of Medicine and the Piedmont Oncology Association in small cell carcinoma of the lung have been analyzed. Of 102 patients evaluable for toxicity, 50 were treated with a combination of cyclophosphamide, adriamycin, and vincristine (CAV) and 52 received this regimen plus VP-16-213. Vincristine dosage was the same in both arms of the study. When analyzed by severity, neurologic complications were similar in both treatment groups: Grade 1-2 neurotoxicity occurred in 55% of patients on both arms and grade 3-4 neurotoxicity was observed in six (12%) patients on the CAV arm and four (8%) on the CAV-VP-16-213 arm. Addition of VP-16-213 to vincristine did not potentiate vincristine-induced neurotoxicity when administered in this dose-schedule relationship.
Adult↗