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Biomedical subjects

R Pazdur

Publications and source records attributed to R Pazdur.

At least 127 records · Page 7Linked to original sources
PubMed1990

A phase II trial of recombinant human interferon-gamma and recombinant tumor necrosis factor in patients with advanced gastrointestinal malignancies: results of a trial terminated by excessive toxicity.

Recombinant human tumor necrosis factor and recombinant human interferon-gamma are two representatives of a novel class of antineoplastic agents. Evaluation of these agents in vitro has suggested that the combination would be more effective than either agent alone. A prior phase I study demonstrated that the maximum tolerated dose for each agent was 150 micrograms/m2/day for 5 days when administered concomitantly. Based on this experience, a phase II trial of patients with biliary tract, pancreatic, and colorectal cancer was planned. Our goal was to treat a minimum of 14 patients with each tumor type. However, in the first 13 patients entered into this trial the toxic effects at the starting doses of 125 micrograms/m2/day for 5 days for each agent were intolerable, with four patients unable to complete planned therapy. In this cohort of patients, no objective responses were observed. Further clinical investigation of this combination should consider alternative treatment schedules to reproduce the in vitro synergistic cytotoxicity of this combination while minimizing host toxicity.

Adolescent↗
PubMed1989

Low-dose continuous infusion 5-fluorouracil. Evaluation in advanced breast carcinoma.

Low-dose continuous infusion 5-fluorouracil (LDCI-FU) was administered to 28 women with advanced breast carcinoma. Daily doses ranged from 175 to 250 mg/m2. The LDCI-FU was delivered continuously until the appearance of toxicity and was reinstituted at a 20% dose reduction after toxicity completely resolved. Patients with a median age of 56 years and a median performance status of 60% (Karnofsky) had been previously treated with combination chemotherapy. Complete responses were observed in two patients with soft tissue metastases. Thirteen patients experienced partial responses with a median duration of response of 4+ months. Partial responses were predominantly observed in soft tissue disease; however, five patients with visceral metastases experienced partial tumor regression. Median survival for the study group was 4+ months. Hormonal receptor status did not predict response to LDCI-FU. Toxicities included stomatitis, ten patients; hand-foot syndrome, eight patients; mild leukopenia, two patients; moderate thrombocytopenia, two patients; diarrhea, three patients; ataxia, three patients. Catheter-related toxicities of sepsis and/or thrombosis occurred in six patients. Because of the demonstrated activity in previously treated patients (53% response rate), LDCI-FU should be investigated in combination chemotherapy regimens in untreated breast cancer patients.

Adenocarcinoma↗
PubMed1989

Metoclopramide versus metoclopramide and lorazepam. Superiority of combined therapy in the control of cisplatin-induced emesis.

Sixty-four patients treated with cisplatin-containing regimens were entered into a randomized, double-blinded study examining the antiemetic efficacy of metoclopramide with and without lorazepam for control of cisplatin-induced emesis. Metoclopramide was administered to all patients at 2 mg/kg, intravenously, 30 minutes before chemotherapy and 1.5, 3.5, and 5.5 hours posttreatment. Patients randomized to receive combined antiemetic therapy were administered lorazepam at 2 mg/m2 (maximum, 4 mg dose) intravenously, 30 minutes before chemotherapy. Those patients not receiving lorazepam were given normal saline placebo. Degree of nausea and number of vomiting episodes were recorded on a data flow sheet with a visual analogue scale. Drug toxicities were evaluated before each administered dose. Patients receiving both metoclopramide and lorazepam experienced significantly less vomiting episodes (P less than 0.05) and nausea (P less than 0.01) when compared to patients given metoclopramide alone. Forty-four percent of those receiving the combined therapy reported no nausea or vomiting episodes compared to only 22% receiving metoclopramide alone. Sedation was significantly more common in patients receiving lorazepam (88%) as opposed to patients receiving only metoclopramide (43%), P less than 0.01. Amnesia was seen in 25% receiving lorazepam. No significant difference in diarrhea, dystonia, or disinhibition was observed between the two arms. The authors conclude that the combination of lorazepam and metoclopramide was superior to metoclopramide alone in the prevention of cisplatin-induced nausea and vomiting, with sedation and amnesia more commonly observed in the combined regimen.

Adult↗
PubMed1989

Pharmacokinetics and toxicity of continuous infusion amphotericin B in cancer patients.

To evaluate the role of amphotericin B (AmB) in the biochemical modulation of antineoplastic agents, AmB was administered as a continuous infusion over a period of 52 to 120 h to 14 patients (26 courses) with advanced carcinomas. Continuous infusion amphotericin B (CI-AmB) was delivered at a rate of 0.5 to 0.8 mg/kg/d (19-31 mg/m2/d). The AmB plateau levels assayed by HPLC ranged from 0.7 to 1.9 micrograms/mL and were directly related to the infusion rate. The AmB plasma disposition was biphasic, with mean half-lives of 17 h for the first phase and 11 d for the terminal phase, and a mean residence time of 12 d. Biochemical modulation of antineoplastic agents (lomustine, doxorubicin, cyclophosphamide) by CI-AmB was not demonstrated clinically. Acute toxicities of fever and chills were noted in only 3 of the 26 courses. Reversible renal toxicity was observed in 23 courses. Therapeutic antifungal plasma levels were rapidly reached and maintained for the duration of infusion, with a reduction of acute toxicities associated with shorter infusions. These observations provide impetus for further clinical investigation of CI-AmB.

Adolescent↗
PubMed1989

Metastatic sweat gland carcinoma: response to 5-fluorouracil infusion.

A 78-year-old white male presented with metastatic sweat gland carcinoma involving regional lymph nodes, pleura, pericardium, and chest wall. A complete response of three months duration was achieved by using a 96-hour infusion of 5-fluorouracil. This is the first report of a complete response to systemic chemotherapy in metastatic sweat gland carcinoma.

Aged↗
PubMed1989

Low-dose continuous infusion 5-fluorouracil and cisplatin: phase II evaluation in advanced colorectal carcinoma.

A study was performed to evaluate the combination of low-dose continuous infusion 5-fluorouracil (LDCI-FU) (300 mg/m2 daily for 28 days) and cisplatin (20 mg/m2 days 1-5 and 24-28). Patients were treated for 28 days with a subsequent 14-day rest period. A total of 24 patients were entered on the study and were evaluable for response and toxicity. All patients were previously untreated, with a median age of 61.5 years and median performance status of 70% (Karnofsky). Bidimensional measurable disease was required. Complete responses were noted in 2 of 24 (8%) patients lasting 8+ and 9 months. Partial responses were observed in 8 of 24 (33%), with a median duration of response of 6 months. Median survival for the 24 patients was 9+ months. Toxicities included nausea and vomiting (25%), hand-foot syndrome (21%), diarrhea (4%), myelosuppression (21%), neurotoxicity (13%), gastric ulceration (13%), mucositis (17%), nephrotoxicity (4%), and subclavian vein thrombosis (21%). This combination demonstrated antineoplastic activity; however, its efficacy parallels other trials utilizing both single agent 5-fluorouracil (5-FU) and different variations of the 5-FU/cisplatin in combination. The impact of this combination on survival and comparison to other regimens requires a randomized trial.

Adenocarcinoma↗
PubMed1988

Acodazole hydrochloride: phase I trial, pharmacokinetics, and evaluation of cardiotoxicity in dogs.

Acodazole (NSC 305884) was examined in a Phase I trial evaluating a 1-h infusion repeated every 21 days in 37 patients with advanced carcinomas. Cardiac toxicity was dose-limiting at 1370 mg/m2, manifested as multiple premature ventricular contractions, QTc interval prolongation, and decreasing heart rate. Other toxicities included mild to moderate nausea and vomiting and local reaction near the i.v. injection site requiring the use of central venous catheters. Antineoplastic activity was not observed. Acodazole levels assayed by high-performance liquid chromatography disclosed a peak plasma level of 19 +/- 4 (SEM) micrograms/ml for 1370 mg/m2. Acodazole plasma levels decreased in a triphasic manner over a 100-fold range. The volume of distribution at steady state was 238 +/- 18 liter/m2 suggesting extensive tissue binding. The total body clearance was 13.6 +/- 0.9 liter/h/m2; the percentage of urinary excretion was 29 +/- 2% for 48 h. To evaluate cardiac toxicity, acodazole was administered to five dogs at 2262 mg/m2 (1-h infusion) which provided plasma concentrations similar to those achieved at 1370 mg/m2 in humans. Consistent findings in dogs were drug-related prolongation of QTc intervals, and reduction in heart rate, left ventricular dP/dt, and mean blood pressures. Clinical development of acodazole requires studies to further elucidate and alleviate this cardiac toxicity.

Aminoquinolines↗
PubMed1988

PCNU: phase II evaluation in advanced colorectal carcinoma.

PCNU, a N-(2-chloroethyl)-N-nitrosourea, was administered to 37 previously treated patients with metastatic adenocarcinoma of the colon and rectum. The drug dose was 100 mg/m2, intravenously, over one hour for good risk patients and 75 mg/m2 for poor risk patients. Poor risk patients were defined as patients over 65 years of age or having liver enzymes greater than twice normal. The infusion was repeated at 6 week intervals. Seventeen patients (median performance status 80%) received PCNU at the 100 mg/m2 dose; 20 patients (median performance status 70%) received PCNU at the 75 mg/m2 dose. Complete responses were not observed. One patient treated with 100 mg/m2 achieved a partial response. Toxicity was primarily hematological with life-threatening leukopenia and thrombocytopenia observed in six patients. PCNU administered in the described dose schedule demonstrated little therapeutic efficacy in this patient population.

Adenocarcinoma↗
PubMed1988

Preoperative radiation and chemotherapy for localized squamous cell carcinoma of the esophagus: a RTOG Study.

Forty-one evaluable patients with localized squamous cell carcinoma of the thoracic esophagus were treated by a course of radiation therapy (3000 cGy in 3 weeks), 5-Fluorouracil (5-FU) and Cis-platinum (Pt). This was followed by an esophagectomy in medically eligible patients who agreed to the procedure and who had no evidence of extrathoracic tumor. If tumor was found in the specimen, an added 2000 cGy of radiation therapy and additional 5-FU and Pt were given. One-year survival was 44%, 2-year survival 15%, and 3-year survival 8%. All 3-year survivors had tumor-free specimens, but one patient with tumor in the thorax and subdiaphragmatic metastasis survived 2 years.

Aged↗
PubMed1988

Linitis plastica of the esophagus.

A 62-yr-old woman was evaluated for a 2-wk history of regurgitation and weight loss. Radiologic studies demonstrated a stenotic region in the distal third of the esophagus. Multiple endoscopic biopsies were nondiagnostic. Esophagectomy and esophagogastrostomy revealed a diffusely infiltrating adenocarcinoma ("linitis plastica") of the distal esophagus, sparing the gastroesophageal junction and stomach. Despite the absence of metastatic disease at laparotomy, the patient developed metastases unresponsive to chemotherapy. The pathologic, radiographic, and endoscopic findings are consistent with primary linitis plastica of the esophagus.

Adenocarcinoma↗
PubMed1987

Phase I trial of spiromustine (NSC 172112) and evaluation of toxicity and schedule in a murine model.

Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.

Animals↗
PubMed1987

Prospective evaluation of adrenal insufficiency in patients with adrenal metastasis.

Fifteen consecutive patients with metastatic carcinoma who demonstrated bilateral adrenal metastasis on abdominal computed tomography (CT) were evaluated by the cosyntropin challenge test. Primary sites of tumors included lung, ten; colon, two; gastric, one; ovarian, one; and unknown primary, one. Bilateral adrenal enlargement was defined as greater than 1 cm on CT scan. Adrenal insufficiency was defined as a failure to increase serum cortisol by at least 5 micrograms/100 ml to a minimum of 15 micrograms/100 ml at either 30 or 60 minutes postcosyntropin. No patient had previously been on corticosteroids. All patients were questioned and examined for symptoms/signs of adrenal insufficiency. Five patients (33%) were found to have adrenal insufficiency based on the cosyntropin test. Of the clinical parameters evaluated, all five patients had nausea, anorexia, and orthostatic hypotension. The clinical onset of adrenal insufficiency was insidious; no patient experienced acute adrenal crisis. We conclude that adrenal insufficiency is not a rare occurrence in patients with metastatic cancer and bilateral adrenal involvement on CT scan.

Adrenal Gland Neoplasms↗
PubMed1987

Phase I study and pharmacokinetics of caracemide (NSC-253272) administered as a short infusion.

A Phase I study of caracemide evaluating a short intravenous infusion repeated every 21 days is presented. Patients were entered at 85 mg/m2 with subsequent escalation levels of 170, 425, 595, and 795 mg/m2. Mild to moderate nausea and vomiting occurred at all dose levels. An apparent allergic reaction was observed at the 425 mg/m2 level. A "burning pain" originating in the mucosal areas of the head and neck, progressing to the chest and abdomen, was noted at the 425 mg/m2 level. Because of this observation, the infusion time was extended to 4 h. At the 795 mg/m2, this toxicity precluded completion of the 4 h infusion. Pharmacokinetic evaluation disclosed blood levels of 0.74-2.31 microgram/ml at the 425 mg/m2 during the 0.5 h infusion. At the same dose for a 4 h infusion time, blood levels were 0.15-0.18 microgram/ml. At 595 mg/m2 administered as a 4 h infusion, blood levels increased to 0.33 +/- 0.14 microgram/ml. The drug was cleared rapidly from the blood compartment with a half-life of 2.5 min and a total body clearance of 11.51/min/m2. No partial or complete response was observed. However, an advanced colon carcinoma patient experienced subjective pain relief with a decrease in carcinoembryonic antigen. The dose-limiting toxicity of caracemide using the 4 h infusion was an intolerable "burning pain" with a maximum tolerated dose of 795 mg/m2. Further characterization of this dose-limiting toxicity is required prior to further clinical evaluation of caracemide.

Antineoplastic Agents↗
PubMed1987

Aclacinomycin A. Phase II evaluation in bronchogenic squamous-cell carcinoma.

Aclacinomycin A (ACLA-A) was administered to 22 patients with metastatic measurable bronchogenic squamous-cell carcinoma in a Phase II trial of the drug. Sixteen patients were fully assessable for response and toxicity. The initial dose of ACLA-A was 85 mg/m2 weekly for 4 consecutive weeks; however, due to severe myelosuppression, the weekly dose was reduced to 65 mg/m2. Fifteen patients were previously untreated. Toxicity was primarily hematological. Complete or partial responses were not observed on this treatment schedule. ACLA-A administered on this schedule lacks therapeutic efficacy in the treatment of patients with advanced bronchogenic squamous-cell carcinoma.

Aclarubicin↗
PubMed1987

Aclacinomycin A. Phase II evaluation in advanced soft tissue sarcoma.

Aclacinomycin A (ACLA-A), an anthracycline antibiotic, was administered in a Phase II study to 20 patients with advanced, measurable soft tissue sarcomas. The dose schedule consisted of 85 mg/m2 intravenous ACLA-A given weekly for 4 weeks followed by a 2-week rest. Because of severe myelosuppression in the initial patients, the weekly dose was reduced to 65 mg/m2. Seventeen patients were fully evaluable for toxicity and response to the drug. Complete or partial responses were not identified. Toxicity was primarily hematological. ACLA-A administered in the above schedule demonstrated no therapeutic efficacy in patients with advanced soft tissue sarcomas.

Aclarubicin↗
PubMed1987

Fludarabine phosphate. Phase II evaluation in advanced soft-tissue sarcomas.

Fludarabine phosphate (NSC-312878) was administered to 23 patients with advanced soft-tissue sarcomas. Patients entered on the study had a median performance status of 80 and had prior chemotherapy restricted to one previous regimen. Dose schedule was 100 mg/m2 in poor-risk patients (creatinine clearance less than 70 cc/min) and 125 mg/m2 in good-risk patients every 3 weeks. No complete or partial responses were noted in the 20 evaluable patients. Median survival was 12 weeks. Leukopenia was the most common toxicity. Fludarabine phosphate in the above schedule failed to demonstrate therapeutic efficacy in this patient population.

Antimetabolites, Antineoplastic↗