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Biomedical subjects

H L Davis

Publications and source records attributed to H L Davis.

171 records · Page 10Linked to original sources
PubMedDate not supplied

Emergence of acute non-lymphocytic leukemia in breast cancer patients.

The appearance of acute non-lymphocytic leukemia (ANLL) in patients with other hematologic and non-hematologic malignancies is now a well recognized syndrome. These patients have an unusual form of leukemia with distinct clinical and morphological features. With improved therapy many cancer patients have experienced prolonged survival and cure. Some of these patients will develop ANLL as a consequence of their previous therapy, or for reasons associated with their primary tumor (host factors or common oncogenic virus). It is also possible that a fraction of these patients will develop the usual form of leukemia (de novo ANLL) that is unrelated to the underlying malignancy. Indeed, a statistical analysis assuming ANLL incidence rates to be unaffected by breast cancer or cancer therapy, predicted the occurrence of three new ANLL cases with a history of breast cancer in Wisconsin per year. Eleven patients with ANLL and a history of breast cancer were seen at the University Hospitals over a ten-year span (1969-1978). Clinical, morphological and cytogenetic features were examined and it was found that five of the eleven patients had features atypical for therapy related leukemia. Indeed, two of the patients had not received breast cancer therapy. The distinction between de novo and therapy related leukemia is important because remission and prolonged survival are more likely in the former and morbidity and mortality associated with therapy are more likely in the latter. We suggest that if features of de novo leukemia exist, despite previous therapy for underlying malignancy, intensive antileukemia therapy should be considered.

Acute Disease↗
PubMedDate not supplied

Phase I trial of ICRF-187 by 48-hour continuous infusion.

ICRF-187 is the D-enantiomer of the racemic antitumor agent ICRF-159 and was selected for clinical trials on the basis of aqueous solubility suitable for iv administration. Eighteen patients with refractory advanced solid tumors received ICRF-187 by a 48-hour continuous iv infusion in 5% Dextrose in Water, USP. The total dose ranged from 200 to 1000 mg/m2/48 hours. Courses were repeated at 22--28-day intervals. The major toxic effect was reversible granulocytopenia, with the nadir on Day 12 and the recovery by Day 22. At a dose of 1000 mg/m2/48 hours, the median nadir total wbc count was 1700/mm3 (range, 1300--2600), and the median nadir granulocyte count was 597/mm3 (range, 270--1300). Platelet count nadirs of less than 100,000/mm3 occurred in only three of 16 courses at this level. Granulocyte toxicity was not cumulative and was less severe in repeated courses (median nadir, 1000/mm3 in courses two and three). Mild nausea, malaise, and three instances of alopecia were the only nonhematologic toxic effects encountered. Compared to other schedules, a continuous 48-hour infusion of ICRF-187 seems to have greater toxic effects for a given total dose, and this may predict greater biologic effect. A starting dose of 1000 mg/m2 by a 48-hour continuous infusion is recommended for phase II trials.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

Phase I trial and pharmacokinetics of acivicin administered by 72-hour infusion.

Acivicin, an L-glutamine antagonist, was administered to 37 evaluable patients with refractory advanced solid tumors in a phase I trial. A total of 67 evaluable 72-hr iv infusions were given at 3- to 4-week intervals. Doses ranged from 3.0 to 90 mg/m2/course. Reversible CNS toxicity was dose-limiting and included lethargy, somnolence, anxiety, hallucinations, and paranoid psychoses. Four of five patients experienced unacceptable CNS toxicity at 90 mg/m2. Three of eight patients experienced reversible diaphoresis and chills without fever at 75 mg/m2, and two had dizziness and ataxia. Hematopoietic toxicity, nausea, emesis, and diarrhea were mild and dose-related. One patient developed a blue-green discoloration of the infusion arm. Serial plasma and urine specimens from 13 patients were assayed for acivicin using a microbiologic method. Peak plasma levels at the end of the 72-hr infusions correlated with dose and ranged from 0.09 to 1.10 microgram/ml. When data from six patients were fitted to a two-compartment open model, alpha-half-life ranged from 1.1 to 63 mins, while beta-half-life ranged fro 338 to 629 mins. Renal clearance ranged from 6 to 24 mL/min, and nonrenal clearance accounted for 58%-83% of the total drug clearance. CNS toxicity correlated with plasma acivicin levels which exceeded 0.9 microgram/ml for greater than 16 hrs, but not with peak plasma levels or with the integrals of the concentration x time curves. Minor responses were seen in one patient with melanoma, in one with epidermoid pulmonary carcinoma, and in two with colon carcinoma. A starting dose of 60 mg/m2/course was recommended for phase II trials, with possible escalation to 75 mg/m2 in the second course if the drug was well-tolerated.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Phase I trial of PCNU administered by 5-day courses.

PCNU was selected for clinical trials based on high activity in both standard and intracisternally transplanted murine tumors. PCNU was administered of five daily to 24 patients with refractory advanced solid tumors by courses of five daily iv injections every 6 weeks. The total dose ranged from 25 to 125 mg/m2/course. The major dose-limiting toxicity was reversible thrombocytopenia, with the nadi at 28-49 days and recovery by 2 weeks later. At a dose of 125 mg/m2/course, the mean nadir platelet count was 77 X 10(3)/mm3 (range, 16-201 X 10(3)/mm3). Recovery time was prolonged with successive courses in four patients, suggesting cumulative toxicity. The mean nadir of leukopenia at this dose was 2.6 X 10(3) cells/mm3 (range, 1.2-5.0 X 10(3) cells/mm3) and tended to occur with a later median at Day 44. Nausea and vomiting were unusually mild for a nitrosourea. Sporadic transaminasemia and elevated LDH may have been related to the vehicle, N,N'-dimethylacetamide. Other major organ toxic effects were not encountered, and there were no objective responses. PCNU was found to be a base-substitution mutagen in the Salmonella typhimurium assay. A starting dose of 125 mg/m2, divided into five daily doses, is suggested for phase II trails in patients with no significant hematologic compromise from prior chemotherapy or radiation, and a dose of 75 mg/m2 is recommended for all others.

Colonic Neoplasms↗
PubMedDate not supplied

Comparisons of Cooperative Group evaluation criteria for multiple-drug therapy for breast cancer.

The variability of response rates and durations for multiple-drug therapy for advanced breast cancer may be due in part to the evaulation criteria of the investigators. To assess the impact on outcome, a single data set comprising the patients registered in Central Oncology Group protocol 7020B was analyzed by the evaluation criteria of the Central Oncology Group, the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Southeastern Cancer Study Group, as well as by a personally derived "flexible clinical interpretation of treatment benefit." The response rates and durations were quite similar by the criteria of all groups except those of the Southeastern Cancer Study Group, which gave lower rates and longer duration. These differences were consistent with the evaluation criteria for each group and confirmed the differences noted in their published reports. When "flexible" criteria were used, the differences deviated from those using strict group criteria. This might explain, in part, reports from single institutions of response rates that were higher than those achieved in cooperative group studies.

Antineoplastic Agents↗