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Biomedical subjects

R T Chlebowski

Publications and source records attributed to R T Chlebowski.

At least 73 records · Page 4Linked to original sources
PubMed1984

Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results.

Of 157 consecutive patients who had histologically diagnosed hepatocellular carcinoma, 52 with a good performance score, bilirubin less than 2 mg/dl, and absence of bloody ascites were treated with a 75-mg/m2 dose of doxorubicin (unadjusted for hepatic function) every 3 weeks in a prospective trial. Forty-six patients were treated in West Africa and six in Southern California. No complete responses were seen and only six patients (11%) achieved partial objective responses. Plasma concentrations of doxorubicin and doxorubicinol (adriamycinol) were determined at four selected time points for up to 72 hours, corresponding to the terminal phase of disposition in eight African patients. The African patient results were compared to those seen in North American patients with hepatocellular carcinoma and other malignancies. In African patients with hepatocellular carcinoma, terminal half-life of doxorubicin was prolonged at 39.8 +/- 15.9 hours. The ratios of the corresponding concentration X time values of doxorubicinol to doxorubicin, which reflect the overall metabolite to parent drug ratio, ranged from 0.7 to 4.6, with a mean ratio of 2.03 +/- 1.20 in the African patients with hepatocellular carcinoma compared to a mean ratio of 0.76 +/- 0.31 in North American patients with other malignancies. Pharmacokinetic findings in hepatocellular carcinoma patients in North America and Africa were similar, reflecting elevation and prolongation of doxorubicinol metabolite relative to doxorubicin in the plasma of patients with this disease from both areas. We conclude that: (a) doxorubicinol disposition is altered in African as well as North American patients with hepatocellular carcinoma; and (b) even when given in full dose to patients with favorable prognostic features, iv doxorubicin has only limited activity against hepatocellular carcinoma.

Adult↗
PubMed1984

Abnormal deoxyuridine suppression as a rapid predictor for antimetabolite chemosensitivity: correlation with in vitro tests of growth inhibition.

The deoxyuridine (dU) suppression test, which estimates the activity of the de novo pathway to DNA synthesis from dU, was evaluated as a predictor of antimetabolite growth inhibition. Observations of growth inhibition were made using flask cell culture and soft agar clonogenic assay and correlated with results of the rapidly performed dU suppression test in human (SK-L7) leukemia cells, in methotrexate-sensitive and -resistant murine (L1210) leukemia cells, and in human tumor explants. The concentration of methotrexate resulting in a positive dU suppression test was closely correlated with the methotrexate concentrations required for growth inhibition in flask and soft agar culture systems. The fact that the dU suppression test can be rapidly interpreted in 4 hours compared to the longer period required for clonogenic assay suggests that further evaluation of this procedure as a rapid predictor for clinical antimetabolite response is warranted.

Animals↗
PubMed1984

Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss.

Thirty-eight patients with advanced cancer and weight loss were tested in a prospectively randomized, double-blind, placebo-controlled trial to evaluate the influence of hydrazine sulfate on carbohydrate metabolism in cancer cachexia. All patients had an initial 3-day inpatient metabolic evaluation including: standard 5-hr p.o. glucose tolerance test, hormone studies, and total glucose production by infusion of [6-3H]glucose. After 30 days of treatment with capsules containing either placebo or hydrazine sulfate in a 60-mg, 3 times/day dosage, inpatient evaluation was repeated. A total of 62 metabolic inpatient evaluations were performed. The pretreatment characteristics of age, sex, prior therapy experience, nutritional parameters and tumor types were comparable in placebo and hydrazine treatment groups. On initial evaluation, abnormal glucose tolerance and increased glucose production were frequently seen. Serial assessment of glucose tolerance showed no improvement after 30 days of placebo treatment. However, the glucose tolerance was significantly improved in patients receiving 30 days of hydrazine sulfate [2-hr glucose; initial 169 +/- 24 (S.E.) mg/dl versus final 128 +/- 12 mg/dl; p less than 0.05]. In addition, the rate of total glucose production was significantly decreased after 30 days of hydrazine sulfate compared to placebo treatment (2.46 mg/kg/min versus 3.07 mg/kg/min, respectively; p less than 0.05). Toxic effects of hydrazine sulfate were minimal. Our results suggest that hydrazine sulfate can influence the abnormal carbohydrate metabolism associated with weight loss in patients with cancer.

Adult↗
PubMed1983

Doxorubicin and CCNU with or without vincristine in patients with advanced refractory breast cancer. A randomized trial.

Thirty-five patients with advanced breast cancer refractory to initial chemotherapy were randomized to receive two-drug doxorubicin-CCNU or three-drug doxorubicin-CCNU-vincristine (VCR) treatment. Doxorubicin (25-40 mg/m2) and VCR (1.4 mg/m2) were given intravenously every 21 days; CCNU (65-90 mg/m2) was given orally every 42 days. Patients with liver or bone marrow metastases initially received the lower range doses. All patients failed prior chemotherapy with cyclophosphamide and 5-FU with or without methotrexate and prednisone; 67% received prior hormonal therapy. Pretreatment patient characteristics were comparable in both groups. Objective responses (greater than 50% reduction in tumor size) were seen in 7 of 18 patients (39%) on the VCR containing arm and in 8 of 17 patients (46%) on the doxorubicin-CCNU arm. Survival was not improved by VCR addition with overall survival on the doxorubicin-CCNU arm, approximately 10% greater at all intervals (median 9.1 versus 7.0 months; not statistically significant). However, neurotoxicity was significantly greater in the VCR arm (36% versus 0%; P less than 0.05). In advanced breast cancer, no benefit to VCR addition was seen in prior randomized studies of first-line combinations where VCR was the treatment variable. Such results, combined with our experience with VCR in a salvage regimen, question the value of VCR addition to combination regimens in advanced breast cancer.

Breast Neoplasms↗
PubMed1982

Dosimetry and preliminary human studies of 18F-5-fluorouracil.

The relative distribution, metabolism and kinetics of 18F containing compounds, following administration of 18F-5-fluorouracil, has been proposed as a prognostic aid in predicting response to 5-fluorouracil chemotherapy. Because 18F has a relatively short physical half-life (t1/2 = 110 min), and the distribution and kinetics of the radiolabeled 5-fluorouracil need to be studied over periods of time that range over several half-lives of the radionuclide, significant quantities of the labeled drug must be administered in order to obtain good counting statistics. The distribution of 18F, following injection of 18F-5-fluorouracil to rats and mice, has been well documented in our previous work. It appears that the distribution of 18F in humans, following administration of 18F-5-fluorouracil is similar to that in rats. We calculated the radiation dose according to the MIRD technique for the eleven main target organs for a reference man. The critical organs, according to these calculations, are the bladder wall, the kidney and the liver, receiving a radiation dose of 729, 184 and 114 mrad per mCi injected, respectively.

Animals↗
PubMed1982

Doxorubicin cytotoxicity enhanced by local anesthetics in a human melanoma cell line.

Local anesthetics may influence cell membrane structure and permeability. An established human melanoma cell line (SHG) derived from malignant ascites was used to evaluate the growth-inhibitory effects of local anesthetics (procaine and lidocaine) as well as of doxorubicin at incubation temperatures of 37.5 degrees C and 40 degrees C. In this system, procaine and lidocaine inhibited growth at 0.82 mg/ml and doxorubicin inhibited growth at 28 ng/ml. Noninhibitory concentrations of procaine (0.64 mg/ml) when combined with noninhibitory concentrations of doxorubicin (10 ng/ml) resulted in marked growth inhibition. Incubating temperatures of 40 degrees C enhanced all effects of procaine and doxorubicin on cell growth. These results suggest that clinically achievable concentrations of local anesthetics enhance doxorubicin cytotoxicity.

Cell Line↗
PubMed1982

Hypogonadism in male patients with metastatic cancer prior to chemotherapy.

Gonadal hormonal function was assessed in 44 adult males with disseminated cancer prior to chemotherapeutic treatment of their cancer by determination of plasma testosterone, free testosterone, and luteinizing hormone (LH) levels. Low values for both testosterone (43% decreased) and free testosterone (66% decreased) were seen in this largely malnourished cancer population, in which 82% of patients were less than 90% of ideal body weight. Four patients of serum testosterone and LH were seen: (a) normal testosterone and normal LH (12 cases); (b) normal testosterone and high LH (13 cases), consistent with early primary hypogonadism; (c) low testosterone and high LH (10 cases), consistent with frank primary hypogonadism; (d) low testosterone and normal or low LH (9 cases), consistent with secondary hypogonadism. Significantly decreased ideal body weight was found in the group with low testosterone and low or normal LH level. We conclude that decreased gonadal hormone secretion is frequently seen in adult males with advanced cancer and malnutrition even prior to chemotherapy treatment.

Body Weight↗
PubMed1982

Clinical and pharmacokinetic effects of combined warfarin and 5-flourouracil in advanced colon cancer.

Twenty-five patients with advanced measurable adenocarcinoma of the colon were treated with 5-fluorouracil (FUra), 15 to 20 mg/kg/week i.v., plus warfarin p.o. at a dosage which maintains therapeutic levels of anticoagulation. Sixty-four % of patients achieved either objective response (20%) or stable disease (44%). Overall median survival was 19.2 months. Three patients (all with intraluminal lesions) developed gastrointestinal blood loss requiring transfusion and discontinuation of anticoagulation. The interaction between warfarin and FUra as measured by plasma levels was investigated in seven rabbits and three patients. Plasma samples were obtained for 2 hr after FUra administration, both before and after anticoagulation with warfarin. FUra was measured by gas chromatography, and warfarin was assayed using a thin-layer chromatographic fluorescence method. In rabbits, prolongation of FUra plasma t1/2 was seen with high (0.6 mg/kg/hr) but not low (0.025 mg/kg/hr) rates of warfarin infusion. In patients, FUra t1/2 was not changed by therapeutic warfarin anticoagulation. Thus, (a) plasma clearance interaction between FUra and warfarin does not occur in patients receiving therapeutic levels of anticoagulation; (b) FUra and warfarin anticoagulation can be safely given and frequently result in stable disease status for patients with advanced colon cancer. Further trials of this combination are warranted in adenocarcinoma of the colon.

Adenocarcinoma↗
PubMed1981

Treatment of advanced breast carcinoma with 5-fluorouracil: a randomized comparison of two routes of delivery.

Fifty-one patients with metastatic breast carcinoma were randomized to treatment with weekly 5-fluorouracil (5-FU) either by mouth or intravenously. Prior treatment included radiation therapy (75%), chemotherapy(27%), and hormonal therapy (86%). Response frequency (tumor reduction greater than or equal to 50%) in the 49 evaluable patients was 24% (6/25) for oral oral vs. 29% (7/24) for intravenous administration. Disease was stable in an additional 13% of patients treated intravenously and 20% of patients treated orally. Median survival was 9.8 months for intravenously treated patients and 12.1 months for orally treated patients (N.S.). A multivariate model of survival, to adjust for imbalance between treatment groups, also showed comparable survival in the two groups. Neither response nor survival was significantly correlated with nadir granulocyte count. Weekly oral 5-FU results in comparable response and survival to 5-FU given intravenously, consistent with a relatively low dose-response relationship for 5-FU in breast carcinoma.

Administration, Oral↗
PubMed1981

Adriamycin and methyl-CCNU combination therapy in hepatocellular carcinoma: clinical and pharmacokinetic aspects.

Twenty-one patients with unresectable hepatocellular carcinoma (hepatoma) were treated with adriamycin (15-45 mg/m2 q21 D) and methyl-CCNU (75-150 mg/m2 q 63 D) with dosage adjusted for hepatic dysfunction. Objective response frequency was 14% with all responses occurring in patients with normal pretreatment bilirubin levels. Median survival of all patients was 87 days. Initial bilirubin levels greater than 2 mg/dl predicted for decreased survival (median 30 days vs. 115 days, P less than 0.05). Only moderate hematologic toxicity was observed. Plasma profiles of Adriamycin and adriamycinol were determined during 11 courses of Adriamycin administration in seven of these patients. Despite moderately elevated transaminase levels (all cases) and bilirubin levels (three cases), plasma Adriamycin profiles in hepatoma patients were not elevated (terminal half-life of 30 hours) and were indistinguishable from that of non-hepatoma patients with normal liver functions. However, delayed appearance of peak levels and prolongation of terminal half-lives were routinely observed for adriamycinol, a major metabolite of Adriamycin. This resulted ina significant increase in the CXT (concentration X time) ratio of adriamycinol/Adriamycin in hepatoma patients compared with nonhepatoma patients (2.36 +/- 2.12 vs 0.76 +/- 0.31, (P less than 0.05). We conclude that the combination of relatively mild toxicity and normal Adriamycin disposition indicates unusual tolerance to Adriamycin therapy for patients with hepatoma and cirrhosis. As a result, severe dosage adjustments of Adriamycin may not be indicated for all such patients having only moderate hepatic dysfunction.

Adult↗
PubMed1981

Factors influencing the interim interpretation of a breast cancer trial: danger of achieving the "expected" result.

Interim analyses of a metastatic breast cancer trial suggested a significant survival benefit for a five-drug combination chemotherapy compared to a single agent sequential treatment. Subsequent analyses failed to support this observation. Factors influencing the interim interpretation of this trial were investigated and found to include: delayed reporting of data in key cases, treatment effect limited to a patient subset, and problems related to achieving the "expected" result.

Antineoplastic Agents↗
PubMed1981

Significance of relapse after adjuvant treatment with combination chemotherapy or 5-fluorouracil alone in high-risk breast cancer. A Western Cancer Study Group Project.

Beginning in 1974, patients undergoing mastectomy at high risk for recurrence (greater than or equal to 4 nodes positive; median, 9.4 positive; range, 4 to 28) were randomized after stratification for menopausal status and radiotherapy to receive either 5-fluorouracil (5-FU, 500 mg/sq m i.v. every week) or cyclophosphamide, 400 mg/sq m; methotrexate, 30 mg/sq m; and 5-FU, 500 mg/sq m (CMF; all given i.v. every 2 weeks) in a 12-month program. All 62 patients remain evaluable with median follow-up now exceeding 70 months (range, 60 to 80 months). CMF significantly prevented early disease recurrence (97% relapse free on CMF versus 75% on 5-FU at 12 months; p less than 0.05) and demonstrated survival advantage during the initial 40-month follow-up. This significance was subsequently lost, and the percentages of relapse free and overall survival after 70 months are: (formula, see text) The apparently paradoxical relationship between relapse and survival on the 5-FU arm was related to survival after recurrence. Survival after recurrence was significantly longer on the 5-FU compared to the CMF arm (median of greater than 38 versus 10 months, respectively; p less than 0.01). These results suggest (a) long-term survival in adjuvant trials cannot be accurately predicted by short-term differences in relapse frequency, (b) survival after relapse may be influenced by the antecedent adjuvant therapy received, and (c) disease relapse does not necessarily preclude long-term survival.

Breast Neoplasms↗
PubMed1980

Treatment of advanced colon cancer with 5-fluorouracil (NSC19893) versus cyclophosphamide (NSC26271) plus 5-fluorouracil: prognostic aspects of the differential white blood cell count.

One hundred twenty-one patients with advanced measurable adenocarcinoma of the colon were randomized for treatment with intravenous 5-fluorouracil (IV 5-FU) alone, 15 mg/kg/week vs. cytoxan, 15 mg/kg/week IV, on day 1 and 5-FU, 15 mg/kg/week IV during weeks 2--5, repeated in a six-week cycle. Age, sex, performance status, and disease free intervals, were comparable in both arms. Response frequency was 11% for treatment with 5-FU alone and 10% for treatment with combination therapy. The median survival time was significantly greater in the 5-FU-alone arm (8.4 months vs. 5.6 months, P less than 0.05). In both arms, survival was correlated with the nadir white blood count (WBC) achieved during therapy (P less than 0.02). Fourteen patients had pretreatment WBC of greater than 12,000/mm3. None of them had fever, bone marrow involvement with tumor, or recognizable infection at study entry. The 14 patients had a median survival time of 2.3 months, significantly shorter than that of patients with normal pretreatment WBC (P less than 0.05). A pretreatment lymphocyte count was available for all patients. No association between this value and either response to chemotherapy or survival time was noted. These results support the superiority of 5-FU to the combination of 5-FU and cytoxan in the treatment of colon carcinoma, and point to the prognostic significance of the pretreatment WBC in this disease.

Adenocarcinoma↗
PubMed1980

Adriamycin given as a weekly schedule without a loading course: clinically effective with reduced incidence of cardiotoxicity.

Three hundred and thirty-six patients with a variety of tumors were treated with Adriamycin given weekly as an iv bolus of 1 mg/kg with subsequent doses adjusted for hematologic toxicity. This weekly schedule, not utilizing a loading course, resulted in only a 20% incidence of stomatitis. The number of evaluable patients and the percent with objective responses (respectively) according to tumor type were: lung (57 patients, 14%); sarcoma (62, 24%); breast (31, 35%); transitional cell carcinoma (17, 29%); non-Hodgkin's lymphoma (17, 29%); head and neck (16, 13%); colorectal (13, 0); ovarian (eight, 25%); and other (53, 11%). These response frequencies are comparable to those reported for every-3-week regimens using 60-75 mg/m2 of Adriamycin. Sixteen patients were given 450-550 mg/m2 of Adriamycin, five were given 550-600 mg/m2, and ten were given greater than 600 mg/m2. None of the study patients developed definite evidence of drug-induced congestive heart failure. Therefore, Adriamycin given as a weekly schedule provides a clinically effective alternative to the every-3-week schedule of administration. The weekly schedule is associated with tolerable toxicity and a decreased risk of developing drug-induced congestive heart failure.

Doxorubicin↗