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Biomedical subjects

D L Trump

Publications and source records attributed to D L Trump.

At least 91 records · Page 5Linked to original sources
PubMed1989

"Eight-drugs-in-one-day" chemotherapy administered before and after radiotherapy to adult patients with malignant gliomas.

Thirty-one adult patients with malignant glioma (23 with glioblastoma multiforme, six with anaplastic astrocytoma, and two with brainstem glioma) were treated with up to ten cycles of "eight-drugs-in-one-day" chemotherapy (methylprednisolone 300 mg/m2, vincristine 1.5 mg/m2 [maximum of 2 mg/cycle], CCNU 75 mg/m2, procarbazine 75 mg/m2, hydroxyurea 3000 mg/m2, cisplatin 90 mg/m2, cytosine arabinoside 300 mg/m2, and imidazole carboxamide 150 mg/m2). Chemotherapy was planned as two cycles before and eight cycles after 60 Gy of involved brain irradiation. A total of 117 cycles of chemotherapy was administered. There was one treatment-related death. Myelosuppression was the most frequent toxic effect (leucopenia was less than 1000/mm3 in 9% of cycles and 1000-2500/mm3 in 25%; thrombocytopenia was less than 100,000/mm3 in 33% of cycles). Sixteen patients developed infections requiring treatment, two of which were life-threatening. Five patients suffered ototoxicity. Nausea and vomiting were observed in 35% of patients. A reversible rise in creatinine was observed in five patients. One patient developed a severe motor neuropathy, and three patients developed mild peripheral neuropathies. Three patients had episodes of atrial fibrillation. One new bundle branch block with supraventricular tachycardia was observed in a patient with pulmonary embolus. Five patients developed thrombophlebitis, three of whom had pulmonary emboli. Two patients suffered strokes in areas anatomically separate from their tumor. Eleven patients declined to continue therapy after receiving an average of three cycles. Two had complete, and five had partial responses. The median survival time was 47 weeks. The responses and survival times observed are comparable to less toxic treatment protocols for adults with malignant gliomas.

Adult↗
PubMed1989

Methotrexate and dipyridamole combination chemotherapy based upon inhibition of nucleoside salvage in humans.

We have carried out a clinical trial in 23 patients to determine whether dipyridamole modulates the clinical effect of methotrexate. This trial was based upon in vitro studies which indicate that dipyridamole potentiates the cytotoxic action of methotrexate through inhibition of thymidine salvage. Methotrexate was given as a bolus injection 24 h after initiation of a high dose dipyridamole infusion. The trial was designed so that methotrexate was escalated in individuals until toxicity occurred and then the methotrexate dose resulting in toxicity was repeated without dipyridamole. During the course of this study the methotrexate dose was escalated from 10 to 130 mg/m2. While individual patient tolerance varied, moderate to severe myelosuppression and/or mucositis occurred frequently in patients receiving the combination with methotrexate doses greater than or equal to 60 mg/m2. Ten of 10 patients who experienced moderate or severe toxicity with the combination had significantly less toxicity when treated with methotrexate alone. Dipyridamole did not increase toxicity by an alteration in methotrexate elimination. The potentiation of methotrexate by dipyridamole in these patients suggests that physiological thymidine levels are sufficient to perturb the clinical effects of methotrexate and that thymidine salvage may represent a mechanism for clinical resistance to methotrexate. These results also suggest that a high dose dipyridamole regimen can be used as a pharmacological approach to test the role of nucleoside membrane flux on the clinical action of other standard chemotherapeutic drugs. Phase II studies testing the clinical efficacy of this combination should use a methotrexate dose of 60 mg/m2 with a provision for methotrexate dose escalation based upon individual patient tolerance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Eight-drugs-in-one-day chemotherapy in postirradiated adult patients with malignant gliomas.

Fifteen patients, 12 with glioblastoma multiforme and 3 with anaplastic astrocytoma, were treated with "eight-drugs-in-one-day" chemotherapy [methylprednisolone 300 mg/m2, vincristine 1.5 mg/m2 (maximum of 2 mg/cycle), CCNU 75 mg/m2, procarbazine 75 mg/m2, hydroxyurea 3,000 mg/m2, cisplatin 90 mg/m2, cytosine arabinoside 300 mg/m2, and imidazole carboxamide 150 mg/m2]. All patients had prior brain irradiation but none had previous chemotherapy. The population included 10 patients with progressive disease after irradiation and 5 who presented within 2 months of completing radiation. Patients received an average of 5 monthly cycles of chemotherapy. Three patients achieved a complete and 2 a partial response (CR + PRrate was 33%). The median survival time was 46 weeks. Myelosuppression was the dose-limiting toxicity. Leucocyte counts between 2.0-4.5 x 10(3)/mm3 were observed in 40% of patients, between 1.0- less than 2.0 x 10(3)/mm3 in 33%, and less than 1.0 x 10(3)/mm3 in 7%. Platelet counts between 50-130 x 10(3)/mm3 were observed in 27% of patients, and less than 50 x 10(3)/mm3 in 33%. Six patients suffered infections, 4 had reversible renal toxicity, 2 developed paresthesias, and one a debilitating myopathy related to treatment with dexamethasone. Ototoxicity was seen in 3 patients. Two patients developed pulmonary emboli. Nine patients had nausea and vomiting, in one case associated with Candida esophagitis. One long-term survivor developed necrosis of the corpus callosum and dementia. Four patients discontinued treatment after an average of 3.5 cycles because of toxicity. Although extremely toxic, this regimen has modest activity in previously irradiated adult patients with malignant glioma.

Adult↗
PubMed1989

A pilot study of short-course, high-dose cytosine arabinoside, etoposide, and cisplatin in refractory, aggressive-histology, non-Hodgkin's lymphomas.

Twenty-three patients with refractory, aggressive-histology, non-Hodgkin's lymphomas were treated with cytosine arabinoside (2.0 g/m2 i.v. every 12 h on days 1 and 2), etoposide (100 mg/m2 i.v. on days 1 and 2), and cisplatin (35 mg/m2 i.v. on days 1 and 2) every 3 weeks. All patients had received one or two prior chemotherapy regimens. Five of 19 (26%) evaluable patients responded, with a median duration of response of 9 weeks (90% confidence interval: 11-48%). One patient with a complete response remains free of disease over 31 months after completing six cycles of therapy. Six transient responses of less than 1-month duration were also observed. Hematological toxicity was significant: 73% of patients experienced grade 4 neutropenia, and 52% experienced grade 4 thrombocytopenia. Twenty patients (87%) underwent dose reductions following their first cycle of therapy for grade 3 or 4 myelosuppression. We conclude that this combination of drugs, when administered by this schedule, has limited antitumor activity; however, administering the regimen with a dose-intense schedule appears warranted.

Adult↗
PubMed1989

High-dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects.

High-dose ketoconazole (400 mg orally three times a day) and physiologic replacement doses of glucocorticoids (hydrocortisone, 20 mg 8 AM, 10 mg 4 PM, and 8 PM) were administered to 38 patients with advanced prostatic cancer, refractory to at least initial testicular androgen deprivation. Thirty patients were completely evaluable; six were withdrawn due to possible ketoconazole-related toxicity and were considered drug failures. Two patients were unevaluable due to intercurrent therapy or inability to maintain follow-up. Ketoconazole was generally well tolerated. Mild or moderate nausea and vomiting occurred in 37% of patients, but required dose modification or discontinuation in only three patients; no hepatic damage was seen. Five of 36 patients (14%) responded to ketoconazole as determined by palpable or radiographic tumor mass reduction of 50% or greater and normalization of acid phosphatase or bone scan. Fifty percent of patients entered were stable at 90 days. Plasma androstenedione and dehydroepiandrosterone sulfate (DHEAS) were reduced markedly in almost all patients. Plasma testosterone (T) levels were low and remained unchanged, while gonadotropins were persistently elevated. Mean plasma ketoconazole content was 6.6 micrograms/mL after 28 days of therapy. While ketoconazole with hydrocortisone does suppress plasma androgens in advanced prostatic cancer patients, this infrequently causes regression of cancer that has progressed despite adequate testicular androgen ablation.

Acid Phosphatase↗
PubMed1988

Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma.

A data base study of 610 patients with recurrent or metastatic renal cell carcinoma was conducted in order to identify clinical characteristics that are prognostic for survival in patients with this disease. Multivariate analysis identified initial Eastern Cooperative Oncology Group performance status (0 versus 1 versus 2 versus 3), time from initial diagnosis (greater than 1 year versus less than or equal to 1 year), number of metastatic sites (0,1 versus greater than 1), prior cytotoxic chemotherapy (no versus yes), and recent weight loss (no versus yes) as important indicators of survival. Closer examination of the resulting model indicated that patients can easily be separated into five prognostic subgroups, the subgroups being defined by a simple function of the number of risk factors present [Eastern Cooperative Oncology Group performance status 1, recent diagnosis (less than or equal to 1 year), greater than 1 metastatic site, recent weight loss, and prior cytotoxic chemotherapy each counting as a single risk factor; and Eastern Cooperative Oncology Group performance status 2 and 3 counting as 2 and 3 risk factors, respectively]. Median survival for each of the five risk groups was 12.8, 7.7, 5.3, 3.4, and 2.1 months, respectively.

Carcinoma, Renal Cell↗
PubMed1988

Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion.

Since this Phase I trial was based on a strategy of biochemical modulation, namely, the inhibition of nucleoside uptake by dipyridamole, a biochemical assessment of the actions of acivicin and dipyridamole was undertaken in order to aid our interpretation of the clinical findings. The primary biochemical objectives of this trial were: (a) to determine whether plasma levels of dipyridamole sufficient to inhibit nucleoside uptake could be achieved with a 72-h continuous i.v. infusion; (b) to monitor the effects of acivicin on two key enzymatic targets, CTP synthetase and GMP synthetase; and (c) to evaluate changes in cellular ribonucleoside triphosphate pools during therapy. Since peripheral blood mononuclear cells have relevant biochemical targets and can be serially obtained during the course of therapy, the biochemical effects of acivicin and dipyridamole were determined in these cells. At the maximally tolerated dose of dipyridamole (23.1 mg/kg/72 h), the steady-state concentrations of total and free dipyridamole averaged 11.9 microM and 27.8 nM, respectively. These levels were sufficient to inhibit cytidine (1 microM) uptake by greater than 50% in the lymphocytes of five of six patients so treated. Using lymphocytes obtained from 14 normal volunteers the concentration of free dipyridamole needed to inhibit the uptake of 1 microM cytidine by 50% averaged 13.8 +/- 1.1 nM. The plasma levels of alpha 1-acid glycoprotein, which tightly binds dipyridamole, ranged from 60 to 300 mg/dl in the patients in this study. As a consequence there were wide variations in the percentage of dipyridamole present as the unbound, pharmacologically active form and in the rates of dipyridamole clearance. The decreased rate of dipyridamole clearance seen in patients with high levels of alpha 1-acid glycoprotein resulted in higher plasma concentrations of total dipyridamole and compensated for the reduced fraction of free drug. Therefore, the plasma concentration of free dipyridamole varied much less than the total drug concentration in these patients. CTP synthetase and GMP synthetase activities were measured in patients' peripheral mononuclear cells prior to and at various times during therapy. CTP synthetase activity was inhibited in a time-dependent fashion by greater than 75% in seven of 13 evaluable courses; GMP synthetase was similarly inhibited in only three of ten cases. Ribonucleoside triphosphate pools were also measured in the patient's lymphocytes. CTP pool reductions of 30 to 50% were seen in nine of 19 courses, but in only four cases was the inhibition greater than 50%.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Phase II trials of 5-day vinblastine infusion (NSC 49842), L-alanosine (NSC 153353), acivicin (NSC 163501), and aminothiadiazole (NSC 4728) in patients with recurrent or metastatic renal cell carcinoma.

One hundred and forty-four evaluable patients with recurrent or metastatic renal cell carcinoma (RCC) were treated with vinblastine infusion (n = 35), L-alanosine (n = 36), acivicin (n = 27), or aminothiadiazole (n = 46). Observed objective response rates of 9%, 3%, 4%, and 2%, respectively indicate that noe of these agents has significant antineoplastic activity in recurrent or metastatic RCC. Multivariate analysis of survival data suggests that initial performance status, time from initial diagnosis to study entry, and the presence or absence of lung metastases are important prognostic factors for survival. After adjustment for these factors, treatment assignment was also seen to be of prognostic value. All four treatments were generally well tolerated. There were no reports of life-threatening or lethal toxicities; however, 37% of the patients experienced severe reactions to treatment, primarily myelosuppression, anemia, neuropathies, and mucositis.

Adult↗
PubMed1988

Intravesical thiotepa versus mitomycin C in patients with Ta, T1 and TIS transitional cell carcinoma of the bladder: a phase III prospective randomized study.

A prospective randomized clinical trial was conducted by the National Bladder Cancer Group to compare thiotepa and mitomycin C in ablating residual Ta, T1 and TIS transitional cell carcinoma of the bladder. Eight weekly instillations were given followed by cystoscopy 4 weeks after the treatment was stopped. The over-all complete response rate based on cystoscopy and either biopsy or cytology was 26 per cent for thiotepa versus 39 per cent for mitomycin C (p equals 0.08). The greatest efficacy was seen in the Ta group with mitomycin C demonstrating superiority over thiotepa. Patients with negative cystoscopy and biopsy but who had positive cytology were considered to be partial responders. When partial and complete responders were combined the over-all response rate was 53 per cent for thiotepa and 63 per cent for mitomycin C (p equals 0.23). Patients with TIS appeared to respond equally to thiotepa and mitomycin C. Toxicity included urinary frequency in 22 of the 73 patients in the thiotepa arm and 31 of the 76 patients receiving mitomycin C. A rash was observed in 2 of the thiotepa group versus 14 of the mitomycin C group. Bone marrow depression occurred in 15 patients receiving thiotepa and in 12 receiving mitomycin C.

Administration, Intravesical↗
PubMed1987

Phase I clinical trial and pharmacokinetic evaluation of acodazole (NSC 305884), an imidazoquinoline derivative with electrophysiological effects on the heart.

Acodazole (NSC 305884) is a synthetic imidazoquinoline which has antimicrobial as well as antineoplastic properties. A Phase I trial of acodazole administered as a 1-h i.v. infusion once weekly X 4 was conducted. Mild to moderate nausea and vomiting and moderate burning and erythema at the infusion site were the only toxicities seen among 33 patients treated over 51 courses at doses between 20 mg/m2/week and 888 mg/m2. The first patient treated at 1184 mg/m2 developed an irregular pulse and was found to have a prolonged cardiac output interval (Q-Ti) on electrocardiogram and polymorphic ventricular tachycardia ("torsades des pointes"). Careful study of five additional patients treated according to a modified schedule (340 mg/m2 week one, 500 mg/m2 week 2, 666 mg/m2 week 3, and 888 mg/m2 week 4) revealed 20% or greater Q-Ti prolongation after 20 of 27 treatments; Q-Ti prolongation had resolved 24-36 h after each infusion. Q-Ti prolongation occurred at all dose levels; no ventricular arrhythmias occurred. Acodazole was cleared with a long t1/2 (20.7 h) primarily by nonrenal mechanisms. No alterations in peak plasma levels or excretion were seen in the patients in whom Q-Ti prolongation was detected. No antitumor activity was seen. Further development of acodazole will require delineation of pharmacological means of surppressing this Q-Ti prolongation.

Adult↗
PubMed1987

Factors influencing options in primary breast cancer treatment.

Primary breast cancer treatment is determined by tumor factors and by patient preference. Breast cancer treatments that preserve the cosmetic appearance of the breast are appealing and effective for appropriately selected patients; long-term survival following tumor excision and breast irradiation appears to be comparable to that for mastectomy. Since April 1981, when a protocol was developed and treatment options were offered, factors influencing treatment selection have been analyzed in 206 consecutive primary breast cancer patients. Mastectomy was dictated by tumor-related factors in 96 patients (47%); 110 patients (53%) had the option of mastectomy or conservation--tumor excision plus radiotherapy to the breast. Among these 110 eligible patients, 54 chose conservation (49%) and 56 chose mastectomy (51%). Intraoperative findings for ten patients electing conservation necessitated mastectomy, so conservation was accomplished for 44 (21%) of those treated for breast cancer. Beginning in July 1982, breast cancer patients took a battery of psychosexual assessments before any operation (Profile of Mood States [POMS], Health Locus of Control Scale [HLCS] Locke-Wallace Marital Adjustment Test [MAT], Psychosocial Adjustment to Illness Scale [PAIS], Derogatis Sexual Function Inventory [DSFI], Millon Clinical Multiaxial Inventory [MCMI], and a Breast Cancer Information Test [BCIT]). Comparisons of psychologic and demographic variables were made between patients who chose mastectomy and those who chose conservation. No demographic variable was statistically significantly related to choice, although older women tended to select mastectomy more than younger women. Compared with those who elected conservation, women who elected mastectomy were more tense and anxious (P less than .01), more introverted (P less than .01), felt more depressed and dejected (P less than .05), and reported more sexual problems (P less than .05). Those who elected conservation valued their physical appearance more highly (P less than .01) and were generally more self-interested (P less than .05). Mastectomy was dictated by medical considerations for approximately half of patients with breast cancer. Among candidates for breast conservation, the importance of retaining the breast appeared to be determined to a significant degree by measurable psychological factors.

Body Image↗
PubMed1987

Zoladex: a sustained-release, monthly luteinizing hormone-releasing hormone analogue for the treatment of advanced prostate cancer.

Zoladex, a sustained-release luteinizing hormone--releasing hormone (LHRH) analogue administered by subcutaneous injection every 28 days, was evaluated at three dose levels in 46 men with untreated advanced prostate cancer. All three Zoladex doses yielded similar endocrinologic effects. After initial transient increases in serum luteinizing hormone, follicle-stimulating hormone, and testosterone concentrations, serum testosterone was suppressed uniformly to castration levels within 22 days. At a median follow-up of 41 weeks, Zoladex had maintained persistent suppression of serum testosterone. Measurements of serum Zoladex levels indicated that release of the drug from the injected depot was sustained over a period of 1 month and that there was no drug accumulation as evaluated over an initial 3-month period. No antibodies to Zoladex were detected. Tumor regression rates and side effects with Zoladex therapy were similar to those reported with daily injections of subcutaneous LHRH therapy. Signs and symptoms consistent with a brief tumor flare after the first injection of the LHRH analogue were noted in eight (17%) of the study entrants. Spinal cord compression was observed in two patients within 1 week from the onset of therapy. Zoladex is considered to be an effective, sustained-release LHRH analogue for the treatment of patients with prostate cancer.

Adenocarcinoma↗
PubMed1987

Platinum analogue combination chemotherapy: cisplatin and carboplatin--a phase I trial with pharmacokinetic assessment of the effect of cisplatin administration on carboplatin excretion.

Cisplatin (NSC 119875) and carboplatin (NSC 241240) are platinum (II) analogues with very different spectra of toxicity. Cisplatin dose is limited by nausea and vomiting, renal dysfunction, and dose-related peripheral neuropathy, whereas carboplatin is myelosuppressive. There are also clinical and laboratory data that suggest that these drugs may not be completely cross-resistant. Therefore, the following phase I trial of combination therapy with cisplatin and carboplatin was undertaken. Since carboplatin toxicity is enhanced in the presence of renal impairment, carboplatin excretion was also evaluated in selected patients at the maximum tolerated dose. Thirty-three patients received 50 mg/m2 cisplatin and doses of carboplatin between 160 mg/m2 and 400 mg/m2. Sequential 20-minute infusions of carboplatin and then cisplatin were able to be administered at the standard doses of carboplatin (320 and 400 mg/m2) with thrombocytopenia to the degree expected if carboplatin alone had been given. However, 280 mg/m2 carboplatin followed by 25 mg/m2 cisplatin/d X 3 caused unexpectedly severe thrombocytopenia in seven of eight patients (median platelet nadir 45,000/microL; range, 12 to 321,000/microL; nadir was less than 90,000 in seven of eight patients). In three patients treated with 280 mg/m2 carboplatin plus 25 mg/m2/d X 3 cisplatin, pharmacokinetics of carboplatin were compared during consecutive monthly cycles without and with cisplatin. Modestly increased areas under the curve (AUC) for carboplatin (15% and 35%) with cisplatin were seen in the two patients who experienced more pronounced platelet suppression with combination therapy. No other limiting or unusual toxicity was seen with this combination. Responses, primarily in "platinum responsive" tumors, were seen. The combination of cisplatin plus carboplatin is feasible and merits further study.

Anemia↗