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Biomedical subjects

A B Benson

Publications and source records attributed to A B Benson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Phase II study of amonafide in the treatment of patients with advanced squamous cell carcinoma of the head and the neck. An Illinois Cancer Center study.

Amonafide (nafidimide), a synthetic organic compound with an inhibitory effect on cellular replication, was used in a phase II study conducted by the Illinois Cancer Center in order to assess its efficacy and toxicity in advanced or recurrent squamous cell cancer of the head and neck. Eligible patients had received no more than one prior adjuvant or neoadjuvant chemotherapy, had normal bone marrow, renal and hepatic function, ECOG performance status of 0-2, and bidimensionally measurable disease. Eligible patients were administered amonafide at a starting dose of 300 mg/m2 for five consecutive days every 3 weeks with dose escalation or de-escalation according to established hematologic criteria in the absence of disease progression. Nineteen of 22 entered patients were evaluable for response and all patients were evaluable for toxicity. Eleven of 19 patients achieved stable disease. Median time to progression after start of treatment was 57 days, for the 18 patients for whom the date of progression is known. There were no partial or complete responses. Hematologic toxicity was dose limiting with grade 3-4 neutropenia in 50 percent of patients and 4 deaths associated with neutropenic sepsis. Non-hematologic toxicity was mild to moderate with nausea and vomiting predominating. In this study, amonafide was a myelotoxic, inactive treatment in advanced/recurrent head and neck cancer. Further use in head and neck cancer appears unwarranted.

Adenine↗
PubMed1995

Phase II trial of etoposide, doxorubicin, and cisplatin combination in advanced measurable gastric cancer. An Eastern Cooperative Oncology Group study.

A phase II study was performed to determine the efficacy and toxicity of the etoposide, doxorubicin, cisplatin (EAP) regimen in the treatment of patients with advanced measurable gastric cancer in a multi-institutional cooperative group setting. Thirty-one evaluable patients with advanced measurable gastric adenocarcinoma were treated with etoposide 120 mg/m2 on days 3, 4, and 5, doxorubicin 20 mg/m2 on days 1 and 8, and cisplatin 40 mg/m2 on days 2 and 9. The treatment was repeated every 28 days. Objective responses were seen in 7 (23%) patients, all achieving partial remissions. Median survival was 9 months for the entire group. Toxicity was mostly hematologic, with grade 3 leukopenia in 26% and grade 4 leukopenia in 55% of the patients. There were 4 treatment-related deaths that were attributable to severe leukopenia and sepsis. Because of the high toxicity and moderate response rate, this regimen is not superior to other less toxic regimens and cannot be recommended for the treatment of advanced gastric cancer outside of an investigational protocol.

Adenocarcinoma↗
PubMed1995

Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial.

PURPOSE: The purpose of this study was to determine the maximum-tolerated dose (MTD) of fluorouracil (5-FU) administered as a protracted intravenous (IV) infusion with concurrent radiation in patients with pancreaticobiliary carcinoma. METHODS: Twenty-five patients with recurrent, residual, or unresectable carcinoma of the pancreas or biliary tract were treated on a phase I trial of protracted IV infusions of 5-FU, beginning at 200 mg/m2/d, concurrent with radiation therapy (59.4 Gy in 33 fractions over 6 to 7 weeks). Chemotherapy began on the first day of radiation and continued through the entire course of treatment. After each cohort of five patients had been treated and observed, the daily dose was escalated in 25-mg/m2 increments until dose-limiting toxicity was encountered. An additional cohort of five patients was treated at the MTD. Clinical examination and computed tomography (CT) were used to evaluate response and patterns of progression. RESULTS: The MTD of 5-FU was 250 mg/m2/d. The dose-limiting toxicity was oral mucositis. The median survival duration of all patients treated was 11.9 months and the 2-year survival rate was 19%. Eleven of 25 patients remain free of local progression and four patients are without evidence of progression at 18+, 18+, 34+, and 44+ months following treatment. CONCLUSION: Concurrent radiation with protracted 5-FU infusion at 250 mg/m2/d is well tolerated and shows evidence of activity against tumors of the pancreas and biliary system.

Adult↗
PubMed1995

Pharmacokinetics and acute cardiovascular effects of menogaril in patients with metastatic tumors.

The new anthracyclin, menogaril [7-(R)-0-methylnogarol], is reported to produce less cardiotoxicity than doxorubicin after multiple doses. This study was designed to assess acute hemodynamic changes during the first administration of menogaril and to relate these changes to plasma concentrations. Menogaril (200 mg/mg) was infused over 90 minutes to 4 patients with metastatic colon or prostate cancer. Cardiac output (CO) and stroke volume (SV) were measured noninvasively by Doppler ultrasound. Menogaril plasma concentrations were measured by HPLC and a 3-compartment mammillary model was used for pharmacokinetic analysis of the results. Steady-state volume of distribution, elimination clearance, and elimination half-life averaged 1,114 +/- 340 l/m2, 38 +/- 16 l/h/m2 and 40.3 +/- 30.3 hours, respectively. All patients were normotensive (baseline blood pressure = 135 +/- 10/73.5 +/- 8 mmHg) and ejection fractions were in normal range (EF = 68 +/- 7%). Transient increase in mean arterial pressure (MAP) from 93 +/- 3 to 107 +/- 4 mmHg (p < or = 0.001) were seen during and shortly after the end of menogaril infusion in all patients. Heart rate (78 +/- 5 min-1) remained constant. CO fell slightly and total peripheral resistance (TPR) increased by 36.8% in the last 2 patients. The increase in MAP was analyzed by a linear-effect model and averaged 0.028 +/- 0.017 mmHg per ng/ml of menogaril in the hypothetical biophase. The half-life for menogaril equilibration between plasma and this biophase was 41 +/- 22 minutes. We conclude that during acute administration of menogaril, blood pressure increases transiently secondary to an increase in TPR.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Pharmacokinetics and pharmacodynamics of oltipraz as a chemopreventive agent.

Oral oltipraz, as a single-dose treatment, was evaluated as a chemopreventive agent in 31 normal subjects. In a subset of subjects, the relationship between plasma oltipraz concentrations and the induction of lymphocyte glutathione (GSH) and glutathione S-transferase (GST) enzyme levels was evaluated. Pharmacokinetic analysis revealed nonlinear disposition of oltipraz with disproportionate 40-fold increase and 9.5-fold decrease in peak plasma concentrations (Cmax) and p.o. clearance, respectively, over the dose range of 100-500 mg. There was no correlation between the oltipraz dose and the absorption rate or the time to reach Cmax. Since oltipraz undergoes extensive metabolism, saturable first-pass elimination could be one of the sources of nonlinearity. Pharmacodynamic evaluation was conducted based on the percentage of elevation of GSH and GST levels over baseline in lymphocytes of subjects receiving 100 mg and 125 mg oltipraz. Induction was observed in both dose groups with a time lag between the maximum concentrations of oltipraz and that of GSH or GST. We also observed a linear correlation between oltipraz Cmax and the corresponding GSH and GST elevations. Subjects with higher Cmax values showed a greater increase over baseline in the GSH and GST levels. Mild toxicities were observed at all dose levels. The most common were flatulence, hunger, fatigue, and headache. These preliminary results indicate that oltipraz may be effective in inducing GSH and GST, an enzyme capable of carcinogen elimination.

Administration, Oral↗
PubMed1994

High-dose aminothiadiazole in advanced colorectal cancer. An Illinois Cancer Center phase II trial.

Thirty-three patients with advanced colorectal carcinoma were entered on a phase II trial of weekly IV aminothiadiazole (175 mg/m2 escalated to 200 mg/m2) with concomitant allopurinol and non-steroidal anti-inflammatory agents (NSAID's). Toxicity was predominantly GI, cutaneous, and chest pain/dyspnea. Twenty-five percent of patients had grade 3 or 4 toxicity. There were no responses in 27 evaluable patients. Median survival was 12 months. Aminothiadiazole, at higher doses than used in previous reports, when given with NSAID's, had no significant activity against large bowel cancer.

Adenocarcinoma↗
PubMed1994

Phase II study of amonafide in gastric adenocarcinoma. An Illinois Cancer Center trial.

Twelve patients with recurrent, metastatic, or inoperable gastric adenocarcinoma were enrolled in an Illinois Cancer Center phase II trial of amonafide (nafidimide), a novel compound that acts as a DNA intercalator. Treatment consisted of a 60-minute infusion of amonafide which was administered daily for 5 consecutive days every 3 weeks at a starting dose of 300 mg/m2/d. Doses were modified according to the grade of toxicity experienced and eight patients underwent dose escalations. All 12 patients were evaluable for response and toxicities were predominantly hematologic. Stabilization of disease for at least 28 days was observed in seven patients and disease progression was noted in five. The median survival was 7.4 months. Doses were sufficient to produce severe bone marrow toxicity in one-third of the patients treated. None of the patients responded to therapy, implying a true response rate less than .221. Based on the results of this study, amonafide showed no activity against gastric adenocarcinoma; however toxicity appeared acceptable at the 300 mg/m2/d x 5 consecutive days every 3 weeks dose and schedule.

Adenine↗
PubMed1994

Phase II study of fludarabine phosphate for gastric adenocarcinoma. An Illinois Cancer Center trial.

In an Illinois Cancer Center phase II trial, fludarabine phosphate was administered to a total of 14 patients (9 men, 5 women) with advanced, measurable, gastric adenocarcinoma. Fludarabine phosphate was given as a rapid intravenous (IV) bolus at a starting dose of 20 mg/m2/d for the first 5 days of a 28-day cycle. For subsequent cycles, the dose was escalated in increments of 2 mg/m2/d, provided that no toxicities greater than grade 1 were noted. In cases of grade 3 toxicity, dose reductions of 2 mg/m2/d were required, and patients who experienced grade 4 toxicities were removed from study. Receiving one complete 5-day course of fludarabine phosphate and surviving for 4 weeks on study were required for a patient to be evaluable for response. None of the patients responded to treatment. Although fludarabine phosphate was ineffective against gastric adenocarcinoma in this study, toxicity was acceptable at the 20 mg/m2/d times 5 every 28 days dose and schedule.

Adenocarcinoma↗
PubMed1994

Lorazepam-enhancement of the antiemetic efficacy of dexamethasone and promethazine. A placebo-controlled study.

This investigation was designed with the objective of improving on currently available antiemetic regimens to counteract the disabling side effects of cancer chemotherapy. The combination of lorazepam, dexamethasone, and promethazine was compared with dexamethasone and promethazine without lorazepam in a double-blind crossover study. The initial study population consisted of 92 women (most with breast cancer) and 7 men; all received moderately or highly emetogenic chemotherapy. Complete data for both periods of therapy were available for 73 of these patients. Crossover analysis showed a highly significant effect of lorazepam in reducing the severity of nausea (p = .003); the severity of vomiting was also reduced, but less dramatically (p = .051). The frequency of all degrees of nausea and vomiting was less with lorazepam, but the difference was not statistically significant. It is concluded that lorazepam added to dexamethasone and promethazine provides an effective regimen for counteracting the emetic side effects of cancer chemotherapy.

Adult↗
PubMed1994

Treatment tolerance of elderly cancer patients entered onto phase II clinical trials: an Illinois Cancer Center study.

PURPOSE: Past research that has compared cancer treatment tolerance between elderly and nonelderly cancer patients has been contradictory. Some investigators concluded that there is no difference between the groups, while others demonstrated elderly patients experienced less tolerance to treatment. As a result, some physicians discriminate against elderly cancer patients by not entering them onto clinical trials out of a belief that they will not tolerate the therapy. METHODS: An analysis was performed using the Illinois Cancer Center (ICC) data base, which contains treatment information for all patients registered onto phase II trials. A maximum of 672 cases was available for evaluation of 11 treatment-related variables. RESULTS: The results demonstrated no significant differences between elderly and nonelderly patients for the following seven treatment-related variables: performance status (PS), number of dose reductions, number of treatment interruptions, total days of delay, best response, reason off-study, and number of grade 3 or greater toxicities. Minor differences were detected for number of courses and number of dose escalations. CONCLUSION: Based on these results, elderly patients should not be denied access to cancer clinical trials relative to age alone.

Aged↗
PubMed1993

A phase II study of continuous infusion 5-fluorouracil in advanced hormone refractory prostate cancer. An Illinois Cancer Center Study.

BACKGROUND: 5-Fluorouracil (5-FU) has been previously associated with therapeutic benefit in hormone refractory prostate cancer. However, no previous study has administered 5-FU as a prolonged continuous infusion, which may be the optimal schedule for this cell-cycle specific agent. METHODS: Therefore, 25 patients were treated with 5-FU administered as a continuous intravenous infusion at a dose of 1000 mg/m2/day for 5 days every 28 days. Eligibility required disease defined by bidimensionally measurable lesions or evaluable lesions on bone scan or radiograph with elevated serum levels of prostate-specific antigen (PSA), no severe cytopenias, and an Eastern Cooperative Oncology Group performance status less than 3. Prior chemotherapy was not allowed. Dose modifications were specified for mucositis and hematologic toxicity. RESULTS: Eighteen of 22 patients were evaluable for response and toxicity, whereas 4 were evaluable for toxicity alone. Toxicity was significant using this dose and schedule and included episodes of sudden death (one patient), paroxysmal supraventricular tachycardia (one patient), and congestive heart failure (one patient). Other Grade 3 toxicities included stomatitis (two patients) and diarrhea (one patient). Significant myelosuppression did not occur. Objective responses were not observed, but 12 patients experienced stable disease with a median duration of 4 months. CONCLUSIONS: Infusional 5-FU can not be recommended for the treatment of advanced hormone refractory prostate cancer.

Aged↗
PubMed1993

Oltipraz: a laboratory and clinical review.

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione; RP 35972] is a synthetic, substituted 1,2-dithiole-3-thione previously used in humans as an antischistosomal agent. Cruciferous vegetables (e.g., Brussels sprouts, cabbage) contain several agents, including dithiolethiones, which appear to inhibit carcinogenesis; however, it is unclear which dietary compounds produce the protective effects. Animal studies have demonstrated that oltipraz is a potent inducer of Phase II detoxification enzymes, most notably glutathione-S-transferase (GST). Laboratory evaluations have shown that dietary concentrations of oltipraz produce marked inhibition of aflatoxin B1-induced hepatic tumorigenesis in rats. Levels of hepatic aflatoxin-DNA adducts, urinary aflatoxin-N7-guanine, and serum aflatoxin-albumin adducts decreased when biliary elimination of aflatoxin-glutathione conjugants increased, thus providing predictive biomarkers that measured a chemopreventive effect. In other animal experiments, oltipraz was found to inhibit chemically induced carcinogenesis in bladder, colon, breast, stomach, and skin cancer models. In addition, oltipraz has been shown to be non-mutagenic, a radioprotector, and a chemoprotective agent against carbon tetrachloride and acetaminophen toxicity. More recent studies in rats suggest that unsubstituted 1,2-dithiole-3-thiones may more effectively inhibit aflatoxin-induced hepatic tumorigenesis and induce electrophile detoxification enzymes. Multiple human clinical trials have been conducted using 1.0-4.5 gram doses of oltipraz over 1-3 days for the treatment of schistosomiasis. Phototoxicity has precluded its use in tropical areas. More recently, a 6 month Phase I trial was completed in which patients with resected colon polyps, or females with first degree relatives with breast cancer, were given oral daily doses of oltipraz at 125 mg or 250 mg. The maximum tolerated dose of oltipraz was < or = 125 mg daily. Grade I/II toxicities included photosensitivity/heat intolerance, GI and neurologic toxicity. Peak plasma concentrations were analyzed by HPLC with wide variability. In another Phase I study, a single oral dose of oltipraz was given to normal volunteers at dose levels of 125, 250, 375, and 500 mg. There was no significant difference in half-life (t1/2) between the four dose levels nor in clearance at the 125 and 250 mg levels. Peak oltipraz levels > or = 1.0 microgram/mL were achievable with marked interpatient variability. A series of small trials evaluating single oral doses of oltipraz for up to 28 days (dosing range 1 mg/kg-3 mg/kg/day) also showed a short t1/2 (4.1-5.3 hours), a sustained steady state without variation after a loading dose, and increased serum and urine concentrations with consumption of a high-fat diet.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer.

PURPOSE: Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer. PATIENTS AND METHODS: Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response. RESULTS: There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients. CONCLUSION: We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.

Adenocarcinoma↗
PubMed1992

Phase II trial of fludarabine phosphate for adenocarcinoma of the pancreas. An Illinois Cancer Center study.

We have conducted a phase II trial of fludarabine phosphate for advanced measurable adenocarcinoma of the pancreas. The drug was administered every 4 weeks by a daily-times-5 bolus schedule beginning at 20 mg/m2/day. No responses were observed in 20 evaluable patients, 18 of whom were previously untreated. Dose-limiting toxicity was leukopenia, and gastroenterologic side effects were frequent. Life-threatening or fatal renal dysfunction occurred in 3 patients. In this schedule fludarabine phosphate is ineffective against adenocarcinoma of the pancreas and appears to have unpredictable severe renal toxicity.

Adenocarcinoma↗
PubMed1991

Oncologists' reluctance to accrue patients onto clinical trials: an Illinois Cancer Center study.

Clinical trials are recognized as the standard of care for the cancer patient, and the randomized, controlled trial represents the most definitive method to determine the effectiveness or ineffectiveness of a cancer treatment. However, less than 3% of all eligible patients enter a clinical trial. Of the 437 physician members of the Illinois Cancer Center (ICC), 244 responded to a survey designed to determine factors that present a significant barrier to entering patients on clinical trials. Rigid protocol design was the primary deterrent to accrual, especially for medical oncologists. Surgeons, radiation oncologists, and medical oncologists differed with respect to several factors, including willingness to seek a clinical trial, tendency to treat patients off study, quality-of-life issues, and the belief that trials were too excessive in time commitment (P less than .05). Compared with hospital-based physicians, community oncologists had fewer patients on trial, were more likely to enter patients on the basis of age, and were more concerned about aspects of informed consent and the financial burden of a trial (P less than .01). One third of the physicians never pursued a clinical trial because of conflict with the priorities of individual care and excessive follow-up time. Fourteen percent indicated that they discouraged patients from participating in a clinical trial due to the risk of a patient receiving a placebo and patient follow-up requirements (P less than .05). Subgroups of physicians differ in their reluctance to accrue patients, and there are clusters of beliefs expressed by physicians concerning their clinical trial activity. Current conduct of clinical trials needs to be reassessed, and intervention studies are required to determine the best methodology to alter physician reluctance to pursue clinical trials.

Attitude of Health Personnel↗
PubMed1990

Phase II study of lonidamine in patients with metastatic breast cancer. An Eastern Cooperative Oncology Group study.

The Eastern Cooperative Oncology Group conducted a phase II study of lonidamine in patients with metastatic breast cancer. The drug was given orally to a maximum daily dose of 340 mg/m2. Forty-two patients were entered on study. One partial response was observed; there were no life-threatening toxicities. The results of this study are compared to two similar phase II trials.

Adult↗
PubMed1989

Phase I trial of hepatic artery infusion of 5-iodo-2'-deoxyuridine and 5-fluorouracil in patients with advanced hepatic malignancy: biochemically based combination chemotherapy.

Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8-14 of therapy, patients received IdUrd as a separate 3-h HAI daily x 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day x 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2'deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (less than or equal to 0.1 microM). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day x 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day x 7.

Animals↗