Biomedical subjects

M J Kellihan

Publications and source records attributed to M J Kellihan.

4 recordsLinked to original sources

PubMed1994

Inefficacy of low-dose continuous oral etoposide in non-small cell lung cancer.

Etoposide is more active in small cell lung cancer when given over 5 days than as a single injection. To examine this concept further, we designed this Phase II study in NSCLC using continuous low-dose oral etoposide. We enrolled 19 patients with measurable disease and the standard eligibility criteria. 16 had no prior chemotherapy. Etoposide was given at a dose of 50 mg by mouth daily. The median duration of therapy was 63 days (14-212 days). Toxicity was mild myelosuppression and GI symptoms. Therapy was discontinued because of progression of disease in 13 patients, toxicity (GI) in 3 patients; intercurrent disease, self-removal, and other reasons in 1 patient each. No complete or partial responses were seen (95% CI: 0-17.6%). The median survival after entry into the trial was 159 days (41-571+ days). We conclude that low-dose continuous oral etoposide is a well-tolerated but ineffective regimen in non-small cell lung cancer.

Administration, Oral↗

PubMed1993

Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A phase I trial.

BACKGROUND: Hydroxyurea is an S-phase specific drug. Constant exposure of tumor cells with a low S-phase fraction to the agent may result in improved cell kill. Because of its short half-life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses. METHODS: Eligible patients had histologically confirmed cancer without effective alternate therapy, normal blood counts, liver and kidney function. After giving informed consent, the infusion began via a permanent indwelling catheter utilizing a portable pump. Dose levels (in g/m2/d) were 0.5 for level I, 1.0 for level II, 1.66 for level III, and 2.5 for level IV. RESULTS: Fourteen patients were entered. Five were men. Median age was 56 years of age (range: 32-67), median performance status 1 (range: 0-2). Diagnoses were as follows: colorectal cancer, seven; unknown primary site, three; breast cancer, two; melanoma, one; and adenoid-cystic carcinoma, one. Nine patients were pretreated with chemotherapy. Three patients were entered per dose level, except on level I, were five were entered. The mean duration of infusion was 12 weeks on level I, 5 weeks on II, 3 on III, 1 on IV. Toxicity included leukopenia below 2.0 K/mm3 in one patient each on levels III and IV, thrombocytopenia below 100 K/mm3 in one patient each on levels II and IV, and stomatitis in three patients (one on level II and two on IV). This toxicity was dose limiting. One patient on level III, with an unknown primary, had an objective response. HU levels were measured by a modification of the Fabricius-Rajewsky method. Mean plasma levels in micrograms per milliliter (SEM) were as follows: level I, 3.6 (0.23); level II, 5.1 (0.57); level III, 10.1 (1.55); and level IV, 16.7 (one point). Fetal hemoglobin rose two-fold and five-fold in two patients on level I after 9 and 16 weeks on therapy, respectively. CONCLUSIONS: HU as a continuous intravenous infusion is well tolerated; the maximum duration of therapy is related inversely with the dose given. No major antitumor activity was seen. The greatest interest in the drug rests in its future use as a modulator and radiation potentiator. The increase in hemoglobin F was of interest and may be important in the treatment of sickle cell disease.

Adult↗

PubMed1992

Pamidronate.

OBJECTIVE: The primary objective of this article is to introduce readers to the use of a new agent, pamidronate. The article discusses its use in hypercalcemia of malignancy (HCM), osteolytic lesions, and Paget's disease. Pharmacokinetic data and clinical trials are reviewed, as well as adverse effects and dosage guidelines. DATA SOURCES: A MEDLINE search was used to identify English-language studies involving pamidronate for the period from 1970 to 1992. STUDY SELECTION: As comparative trials were few in number, trials using pamidronate as a single agent were also reviewed. DATA EXTRACTION: Sparse pharmacokinetic data were obtained from clinical trials. All clinical trials available at the time of publication that met the following criteria were reviewed: (1) allowed for adequate rehydration prior to drug therapy; (2) reported standardized and corrected serum calcium concentrations; (3) separated data obtained from patients who received pamidronate alone from those who received pamidronate and concurrent chemotherapy. RESULTS: Pamidronate has a pharmacologic profile similar to that of etidronate, but pamidronate is more potent and has a longer duration of effect. It has been investigated primarily in the treatment of HCM as well as in the treatment of osteolytic bone metastases and Paget's disease. In hypercalcemia of malignancy it appears to be as effective as established agents with the advantage that a single dose of pamidronate 90 mg iv provides a durable response. In Paget's disease chronic oral administration has also been shown to be effective in relieving bone pain. Adverse reactions with intravenous administration are transient and self-limiting and usually occur with the first dose. The most common adverse effect is a transient and self-limiting fever. Chronic oral administration of doses greater than 600 mg/d is associated with gastrointestinal toxicities. CONCLUSIONS: Although more well-designed clinical trials comparing pamidronate with standard therapies and other available agents are necessary, initial results indicate that pamidronate is an effective and promising alternative for use in the treatment of HCM.

Bone Neoplasms↗

PubMedDate not supplied

Drug formulary review process for sargramostim and filgrastim: focus on analysis of adverse drug reactions.

Selection of a drug for formulary inclusion involves evaluation of safety, efficacy, and cost. The colony-stimulating factors (CSFs) sargramostim and filgrastim have a broad range of potential indications and represent a costly formulary addition when acquisition price alone is considered; their comparative safety is unclear. These factors suggest that the CSFs should be closely scrutinized prior to formulary addition. In the absence of direct comparative studies, an assessment of the safety of CSFs involves evaluation of information provided in the product circular, official drug compendia, adverse biologic reports submitted to the United States Food and Drug Administration, and data from key clinical trials. Data in the product circulars report on adverse events in small numbers of patients treated for chemotherapy-induced neutropenia (filgrastim) or neutropenia subsequent to bone marrow transplantation (sargramostim). The official compendia and clinical trials include experience with CSFs produced in a variety of expression systems; these data are not limited to sargramostim and filgrastim. Importantly, there was a similar incidence of adverse events in patients who received sargramostim or filgrastim and in those who took placebo reported in the product circulars and the pivotal trials, suggesting that the underlying disease may have an important role in determining the side-effect profile of these agents. Adverse biologic reports represent experience with sargramostim and filgrastim obtained under actual clinical conditions and suggest that the same types of adverse events are seen with sargramostim as with filgrastim. This analysis suggests that a decision to select filgrastim over sargramostim for formulary inclusion based on the safety profile is not appropriate because currently available data are equivocal and that such decisions would more appropriately be based on efficacy and cost.

Adverse Drug Reaction Reporting Systems↗