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
D R White
Publications and source records attributed to D R White.
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↗
Foamed epoxy resin-based lung substitutes.
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Electrons↗
The composition of body tissues.
A reassessment of the composition data given by ICRP (1975) has been completed, augmented with results from appropriate recent studies. The water, lipid, protein, carbohydrate and ash contents, together with elemental compositions, mass and electron densities are given here for 56 body tissues. Seven tissues (adipose tissue, heart, kidney, liver, mammary gland, muscle--skeletal and skin) had sufficient measured data to enable the spread in the results to be evaluated. All the compositions presented apply to healthy, adult humans, except for some new material on the bones of children.
Body Composition↗
The aetiology of preterm labour.
Factors associated with spontaneous preterm birth were analysed in 254 primigravidae who gave birth to singleton infants between 28 and 36 completed weeks gestation in Aberdeen City District between 1978 and 1982. In 144 women labour followed premature rupture of the membranes and in 110 the membranes were intact and labour began with contractions. Among those with intact membranes, unmarried women and teenagers were over represented to a significant extent compared with all primigravidae. Among those with premature rupture of the membranes, the distribution of age and marital state was similar to that in all primigravidae, but the birthweight centile distribution showed a significant shift towards light-for-dates babies. It is argued that there may be two distinct categories of pregnancies that end in spontaneous preterm labour.
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↗
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↗
Sequential high-dose ara-C and asparaginase in the therapy of previously treated and untreated patients with acute leukemia.
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Aging↗
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↗
Improved tolerance of vincristine by glutamic acid. A preliminary report.
In a murine model system, glutamic acid has demonstrated host protective properties during administration of vincristine (VCR). Subsequently, glutamic acid has been evaluated in patients receiving VCR during adjuvant chemotherapy for stage II carcinoma of the breast. The cumulative VCR dosage and toxicities incurred in 16 patients receiving glutamic acid have been compared to those observed in 88 patients who previously received VCR without glutamic acid in the same chemotherapy program. All patients received VCR 1.0 mg/m2 weekly for 6 weeks with dose modification for neurotoxicity. Treatment patients received glutamic acid 1.5 grams p.o. daily in three divided doses during the induction course. Of the 16 treatment patients, 9 (56%) received 100% ideal dosage of VCR during induction therapy whereas only 24 of 88 (27%) comparison patients attained this dosage level (p less than .025). Gastrointestinal and hematologic toxicities were similar in both groups. These preliminary results suggest the need for an expanded trial of this agent during administration of VCR.
Antineoplastic Combined Chemotherapy Protocols↗
Marked elliptocytosis and schistocytosis in hematopoietic dysplasia.
A 78-year-old white male patient presented with anemia characterized by marked elliptocytosis and schistocytosis. Other morphologic findings in the peripheral blood and marrow were diagnostic of hematopoietic dysplasia (preleukemic syndrome). Five years previously elliptocytosis and schistocytosis were not present, and the only features suggesting hematopoietic dysplasia were significant numbers of micromegakaryocytes in the marrow and rare giant platelets with giant granules in the peripheral blood. The features of this case suggest that acquired marked elliptocytosis and schistocytosis may be an unusual manifestation of hematopoietic dysplasia.
Aged↗
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↗
VP-16-213 in combination chemotherapy with chest irradiation for small-cell lung cancer: a randomized trial of the Piedmont Oncology Association.
The role of etoposide epipodophyllotoxin (VP-16-213) in a combined modality treatment program incorporating local chest irradiation and combination chemotherapy with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and vincristine has been evaluated in a randomized trial of 165 patients with small-cell lung cancer. The overall response rate (complete response [CR] plus partial response [PR]) was significantly greater in the VP-16-213 arm (85% v 64%, P = .005) primarily as a consequence of improved response in patients with extensive disease (85% v 38%, P = .002 and 30% v 8% for CR only, P = .045). No differences in the response rates were observed in limited disease. The duration of response (months) was greater in the VP-16-213 arm (8.6 v 7.0 overall and 14.4 v 11.5 for CR) but not significantly so. Median survival times (months) were consistently greater in the group receiving VP-16-213 when analyzed according to extent of disease and response (10.6 v 9.5 overall; 15.0 v 13.6 for limited disease; 9.0 v 6.7 for extensive disease; 18.5 v 16.2 for CR overall; and 18.6 v 16.1 for CR in limited disease); the results were not statistically significant. The median survival of extensive disease patients attaining a CR was 15.3 months (range 3.2 to 34.3 + months) in the VP-16-213 arm and 7.4+ and 8.1+ months for the two patients with CR in the other group. Anemia and leukopenia occurred to a greater degree in the four-drug regimen, but no unusual or significant compounding toxicity (ie, neurotoxicity) was observed otherwise. Further investigation of this agent in combination chemotherapy programs for small-cell lung cancer appears to be warranted.
Adult↗
A comparative study of radiation safety practices at selected hospitals in the UK and USA.
The radiation safety practices in a group of 25 UK and USA hospitals have recently been assessed. This took the form of detailed inspections of some 62 medical radiation departments, including Diagnostic X-ray, Radiotherapy, Nuclear Medicine and Pathology/Research (Radionuclide) Departments. Empirical expressions called "Radiation Safety Indices" were devised to evaluate the incidence of personal doses and radiological incidents occurring from 1977-82 and to characterise the safety facilities, procedures, supervision and educational techniques in each department. An outline is given of national legislative material and voluntary codes of conduct, together with the results of the departmental inspections. The computed indices are presented graphically and an analysis given of apparent national trends.
Accident Prevention↗
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↗