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R L Heideman

Publications and source records attributed to R L Heideman.

At least 55 records · Page 3Linked to original sources
PubMed1993

A phase II evaluation of thiotepa in pediatric central nervous system malignancies.

BACKGROUND: Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in plasma. This provides a strong rationale for testing this agent against brain tumors. METHODS: Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 65 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. RESULTS: Three of 13 assessable patients with medulloblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 16 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in these respective strata had prolonged periods of stable disease (SD) lasting from 12 to more than 33 weeks. Nine assessable patients with ependymoma had no objective response, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encountered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitrosourea therapy. CONCLUSIONS: By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent.

Adolescent↗
PubMed1993

Relation of tumor-cell ploidy to survival in children with medulloblastoma.

PURPOSE: To assess the value of tumor-cell ploidy as a predictor of survival in medulloblastoma. PATIENTS AND METHODS: Ploidy determinations were based on the flow-cytometric analysis of cellular DNA content in fresh tumor specimens taken from 34 consecutively treated children with newly diagnosed medulloblastoma. Patients were assigned a high or low risk of failure depending on tumor size and invasiveness, and the presence or absence of metastatic disease. Treatment consisted of radiotherapy, with or without chemotherapy, according to institutional or cooperative group protocols. RESULTS: Univariate analysis of candidate prognostic factors showed that only tumor-cell ploidy and clinical risk group had a statistically significant influence on survival. Patients with hyperdiploid stem lines (n = 9) had significantly longer survival times (P = .04) than did those with diploid lines (n = 20). The estimated 5-year survival probabilities (+/- SE) for these two subgroups were 89% +/- 11% and 48% +/- 13%, respectively. Although clinical risk status (high v low) showed essentially the same predictive strength as ploidy, the two features identified largely nonoverlapping subgroups. Thus, within the clinical high-risk group, it was possible to distinguish hyperdiploid patients whose 5-year survival rate (83% +/- 15%) was comparable to that of patients with localized, low-risk tumors. CONCLUSION: This prospective study indicates that both ploidy and clinical risk group are important prognostic factors in medulloblastoma. Their combined use at diagnosis would distinguish patients who require more aggressive therapeutic intervention (diploid, clinical high-risk group) from those who could be expected to benefit most from standard treatment.

Adolescent↗
PubMed1993

High-dose chemotherapy and autologous bone marrow rescue followed by interstitial and external-beam radiotherapy in newly diagnosed pediatric malignant gliomas.

PURPOSE: Evaluation of high-dose chemotherapy with autologous bone marrow rescue (ABMR) in pediatric malignant gliomas. PATIENTS AND METHODS: Newly diagnosed (n = 11) and recurrent (n = 2) malignant glioma patients received high-dose chemotherapy within 4 weeks of surgery; three had near total and 10 had subtotal resection/biopsy. High-dose thiotepa (300 mg/m2) and cyclophosphamide (2 g/m2) daily for 3 days were followed by ABMR; response was evaluated at day 30. At day 60, patients with at least stable disease received hyperfractionated (n = 9) or conventional external-beam radiotherapy (n = 2) preceded by local radioactive iodine 125 implantation (n = 2) or radiosurgery (n = 1). RESULTS: Grade III and IV toxicities after ABMR consisted of mucositis (n = 12), cardiomyopathy (n = 1), acute abdomen (n = 1), pneumonitis (n = 2), and infection (n = 2). One complete and three partial responses were observed; the objective response rate was 31% (95% confidence interval, 9% to 61%). Seven had stable disease, one had disease progression, and one died of toxicity before response evaluation. The median overall and progression-free survival durations after combined modality therapy were 14 months (range, 4 to 30+) and 9 months (range, 0 to 30+), respectively. One patient remains progression-free at 30+ months. Radionecrosis and white matter changes occurred in three patients: one after hyperfractionated irradiation, and two after 125I implants. CONCLUSION: For patients with bulky residual disease after surgery, survival with this aggressive chemotherapy and radiation regimen is not better than that reported for conventional treatment regimens.

Adolescent↗
PubMed1992

Neuraxis dissemination in pediatric brain tumors. Response to preirradiation chemotherapy.

Of 29 consecutive children treated for malignant primary tumors of the central nervous system (CNS) at this institution, postoperative examination showed radiographic or cytologic evidence of neuraxis dissemination in 10 (34%). Given the historically poor results in disseminated CNS tumors treated with surgery and radiation therapy alone, these ten patients were treated prospectively with an investigational Phase II protocol consisting of preirradiation cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 3 and 4). The diagnoses included medulloblastoma (n = 4), malignant glioma (n = 3), cerebral primitive neuroectodermal tumor (n = 1), pineoblastoma (n = 1), and mixed glioma of the brainstem (n = 1). Postoperative neuraxis scanning with computed tomography, magnetic resonance imaging, or spinal myelography showed measurable intracranial or spinal metastases in all children. The cerebrospinal fluid (CSF) cytologic examination was positive for tumor cells in five. The best responses, based on serial imaging of neuraxis metastases, included two complete responses, four partial responses, and three stable disease states. One patient had progressive disease at the primary site despite stable disease in the spine; progressive neuraxis disease was documented in only one patient during chemotherapy. Clearance of tumor cells from the CSF was documented in three patients. The adverse effects of chemotherapy, consisting of transient myelosuppression and mild ototoxicity, were minimal. Reversible neurologic deterioration occurred in two patients; one patient became acutely quadriplegic after a prolonged convulsive seizure without radiographic evidence of tumor progression.

Adolescent↗
PubMed1991

Mephenytoin phenotyping: lack of haematologic effect and timing of urine collections.

Mephenytoin is the prototype substrate for the genetically regulated, polymorphically distributed cytochrome P450, mephenytoin hydroxylase. Mephenytoin is an anticonvulsant which has been associated with leukopenia when used chronically. The haematologic effects of a single dose of oral mephenytoin, as is typically used to determine drug metabolism phenotype for this polymorphism, have not been reported. We administered 100 mg oral racemic mephenytoin to 30 healthy male volunteers and measured complete blood count three times weekly for 23 days. The time dependency of the urinary ratio of S to R mephenytoin in five serial urine samples (0-4, 4-8, 8-16, 16-24 and 24-32 h after the dose) was evaluated. There were no significant decreases from baseline in any subject in leukocyte count, haematocrit or platelet count. Two of the 30 subjects both of Indian extraction, were poor metabolizers of mephenytoin. The S:R ratio decreased with time (p = 0.001). Using the 0-4 h urine, one subject would have been misphenotyped as a poor metabolizer; phenotype assignments were in agreement with each other based on all subsequent urine collections. We conclude that there is no evidence that single dose mephenytoin is associated with haematologic toxicity in healthy male volunteers, and that the 4-8 h post-dose urine is as reliable as the 24-32 h collection for assignment of phenotype.

Adult↗
PubMed1990

Pharmacokinetics and metabolism of cyclopentenyl cytosine in nonhuman primates.

The plasma and cerebrospinal fluid pharmacokinetics of cyclopentenyl cytosine (CPE-C) were studied following i.v. bolus and continuous i.v. infusion in male rhesus monkeys. Following an i.v. bolus dose of 100 mg/m2 plasma elimination of CPE-C was biexponential with a mean t1/2 alpha of 8.4 min, a mean t1/2 beta of 36 min, and a total clearance (CLTB) of 662 ml/min/m2, which is 5- to 10-fold higher than clearance rates in rodents and dogs. Less than 20% of the total dose of CPE-C was excreted unchanged in the urine. The remainder was excreted as the inactive deamination product cyclopentenyl uridine (CPE-U). The ratio of the areas under the plasma concentration versus time curves of CPE-U to CPE-C was 7.0 +/- 2.4 following i.v. bolus CPE-C. The cerebrospinal fluid:plasma ratios of CPE-C and CPE-U were 0.08 and 0.30, respectively. Continuous i.v. infusion of CPE-C was compared to continuous infusion of 1-beta-D-arabinofuranosylcytosine in two monkeys. Steady state plasma concentrations, normalized to a dose of 12.5 mg/m2/h of CPE-C and an equimolar dose of 1-beta-D-arabinofuranosylcytosine, were 2.1 and 0.53 microM, respectively. The steady state concentrations of their corresponding uridine metabolites (CPE-U and 1-beta-D-arabinofuranosyluridine) were 8.2 and 15.5 microM. The rapid elimination of CPE-C by deamination in the primate resulted in a much higher CLTB and considerably lower total drug exposure than in rodents and dogs that clear CPE-C at a much lower rate by renal excretion. These significant interspecies differences in the disposition of CPE-C should be considered in the selection of a starting dose and schedule for human trials and suggest that a pharmacologically directed dose escalation scheme should be used in the planned phase I studies.

Animals↗
PubMed1989

Phase I trial and pharmacokinetic evaluation of fazarabine in children.

A phase I trial of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine, NSC 281272) administered as a 24-h continuous infusion was performed in 16 children with refractory malignancies. Dose-limiting toxicity consisting of reversible granulocytopenia and thrombocytopenia was observed in 4 of 4 solid tumor patients treated at the starting dose of 20 mg/m2/h. Subsequent patients were treated at a dose of 15 mg/m2/h which was determined to be the maximum tolerated dose. Moderate nausea and vomiting were the only other toxicities observed. Plasma steady-state concentrations of fazarabine were attained by 2-4 h in all patients and were 1.8 and 2.5 microM at the 15- and 20-mg/m2/h doses, respectively. The total body clearance of fazarabine was 571 and 550 ml/min/m2 at the 15- and 20-mg/m2/h doses, respectively. In three of four patients evaluated, fazarabine was detectable in the cerebrospinal fluid (CSF). Steady-state CSF concentrations ranged from 0.29 to 0.74 microM in these three individuals and the steady-state CSF:plasma ratios ranged from 0.22-0.25. Both the plasma and CSF steady-state concentrations were within the 0.1 to 1 microM range reported to be cytotoxic in vitro against the Molt-4 human T-lymphoblastic leukemia cell line. Based on the above, the optimal dose for phase II trials of fazarabine administered as a 24-h infusion is 15 mg/m2/h (360 mg/m2/day).

Antimetabolites, Antineoplastic↗
PubMed1989

Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa.

A Phase I trial of thiotepa (TT) administered as an i.v. bolus was performed in 19 children with refractory malignancies. The starting dose was 25 mg/m2 with escalations to 50, 65, and 75 mg/m2. Seven additional patients were treated with 8-h infusions at 50 or 65 mg/m2. The maximum tolerated bolus dose was 65 mg/m2. Reversible myelosuppression was the dose-limiting toxicity. The plasma and cerebrospinal fluid (CSF) pharmacokinetic parameters of TT and its major active metabolite tepa (TP) were also evaluated. When the bolus or infusion methods of TT administration were compared, there was little difference observed in any pharmacokinetic parameter for either TT or TP. The plasma disappearance of TT was rapid and biphasic with half-lives of 0.14 to 0.32 and 1.34 to 2.0 h. Dose-dependent pharmacokinetics was demonstrated by steadily declining plasma clearance with increasing TT dose. Clearance values declined from 28.6 liters/m2/h at the 25-mg/m2 dose to 11.9 liters/m2/h at the 75-mg/m2 dose. The half-life of TP was longer than that of TT and ranged between 4.3 and 5.6 h. There was evidence of the saturation of TP production. TT and TP both exhibited excellent penetration into the CSF, producing lumbar and ventricular concentrations which were nearly identical to simultaneous plasma concentrations. In one patient with a Rickham reservoir, the CSF:plasma area under the (concentration x time) curve ratios for TT and TP were 1.01 and 0.95, respectively. The above data indicate that TT can be safely administered to pediatric patients at doses higher than conventionally used. The favorable CSF penetration of TT and TP suggests that Phase II studies of TT be considered in patients with central nervous system tumors.

Adolescent↗
PubMed1988

Preclinical pharmacology of arabinosyl-5-azacytidine in nonhuman primates.

The plasma and cerebrospinal fluid (CSF) pharmacokinetics of arabinosyl-5-azacytidine (AAC) were studied in rhesus monkeys following a 15-min, 1-h, or 12-h i.v. infusion of 200 mg/kg. No clinically significant toxicity was observed with these schedules. The plasma elimination of AAC is rapid and characterized by a triphasic decay with t1/2 alpha = 3.6-5.4 min, t1/2 beta = 18-24 min, and t1/2 gamma = 94-144 min for the above infusion schedules. The CSF penetration of AAC as measured by the CSF:plasma Css ratio for the 12-h infusion was 0.15. The stability of AAC in pooled plasma, phosphate buffered saline, and RPMI 1640 culture media at 37 degrees C was compared with the terminal half-life of AAC observed in vivo. The shorter in vitro AAC half-life in plasma with or without tetrahydrouridine versus that in phosphate buffered saline suggests that the terminal half-life of AAC in vivo is most likely a result of enhanced nucleophilic attack and hydrolytic degradation of the unstable triazine ring in plasma. A triexponential equation modeling the disappearance of AAC was constructed from the in vivo experimental data. Use of this equation in computer-aided simulations of current Phase I doses and schedules of AAC correctly predicts the human plasma concentrations which have been observed. The preclinical pharmacokinetic data provided here may be useful in helping to develop rational human studies with specific concentration x time goals.

Animals↗
PubMed1988

A pediatric phase I and pharmacokinetic study of spirohydantoin mustard.

A pediatric Phase I and pharmacokinetic study of the lipophilic alkylating agent spirohydantoin mustard (SHM) was conducted in 23 patients. The dose-limiting toxicity of SHM was neurological with disorientation, delirium, or hallucinations occurring in 9 of 23 patients. These symptoms were partially reversible and preventable with physostigmine. In 17 patients who were evaluable for response to treatment (14 of whom had central nervous system malignancies), no objective tumor responses were observed. Pharmacokinetic evaluation of SHM revealed a t1/2 alpha of 1.7 +/- 0.7 min, t1/2 beta of 16 +/- 8.3 min, and total body clearance of 2134 +/- 735 ml/min/m2. Measureable peak plasma levels were less than 40% of that which produces cytotoxicity in vitro against monolayer cultures of rat 9L brain tumor. Over 90% of SHM was protein bound, greatly limiting the free drug available for central nervous system penetration. SHM cerebrospinal fluid to plasma ratios were less than 0.047. The above suggests that in spite of its lipophilicity, SHM may not reach clinically significant levels in the central nervous system at clinically tolerable doses.

Adolescent↗
PubMed1987

Results of a pilot study of hyperfractionated radiation therapy for children with brain stem gliomas.

The majority of children with brain stem gliomas develop progressive disease within 18 months of diagnosis and treatment. Radiotherapy (RT) is of transient benefit in most patients and higher total doses of RT have been related to improved survival. The amount of RT which can be given is limited by the tolerance of the surrounding brain. Hyperfractionated RT theoretically allows higher doses of RT to be tolerated by the brain. Sixteen children with brain stem gliomas were treated on a hyperfractionated RT schedule, receiving 120 cGy of RT twice daily, to a total dose of 6480 cGy. All patients tolerated treatment well. Eleven of 15 (73%) evaluable patients had a response to treatment and two (13%) others had stable disease. One patient developed progressive disease during treatment. All patients were tapered off steroids by the completion of treatment. Thirteen of 16 (81%) patients developed progressive disease at a median of 7 months after diagnosis and three remain in remission 8, 12, and 15 months following diagnosis. These results were similar to those of historical controls. Two patients were surgically explored at time of relapse and 5 have had an autopsy. No acute or subacute neurologic toxicity was seen; but long-term detrimental effects on brain could not be assessed. The implications of this study are that escalations of the dose of hyperfractionated RT can be entertained for children with brain stem gliomas.

Adolescent↗
PubMed1987

Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia.

The disposition of the synthetic corticosteroids, dexamethasone and prednisolone, in CSF was evaluated following bolus intravenous (IV) and intrathecal (IT) injection in a nonhuman primate model. Steroid concentration in plasma and CSF was measured with a radioimmunoassay following celite column chromatography. The CSF to plasma ratios of dexamethasone and prednisolone following IV bolus administration were 0.15 +/- 0.02 and 0.08 +/- 0.03, respectively. Although peak levels of the two steroids in the CSF reached equally potent levels when administered systemically in equipotent doses, the half-life of prednisolone in the CSF was shorter. In addition, there was a significant difference in the plasma protein binding of the two steroids, which may account for the differences in their CSF pharmacokinetics. Dexamethasone was 70% protein bound over a wide concentration range, while the protein binding of prednisolone was concentration dependent, ranging from 60% at 10 mumol/L to 95% at 0.5 mumol/L and below. After the initial distribution phase in plasma, CSF concentrations of dexamethasone and prednisolone approximated free plasma concentrations, indicating that penetration into the CSF was limited primarily by protein binding. At the plasma concentrations achieved following oral administration of standard doses of prednisone in children, the prednisolone (the active metabolite) is greater than 90% protein bound. The proportionally higher free plasma levels of dexamethasone result in greater penetration into the CSF. These findings may explain the lower rates of meningeal leukemia observed in children receiving dexamethasone instead of prednisone for the treatment of acute lymphoblastic leukemia (ALL).

Animals↗
PubMed1987

Eight drugs in one day chemotherapy for brain tumors: experience in 107 children and rationale for preradiation chemotherapy.

The development of a new multidrug chemotherapy regimen for primary brain tumors was based upon the cellular heterogeneity within individual tumors, the Goldie-Coldman and Price-Goldie-Hill hypotheses, and known agonistic effects of certain drug combinations and sequences. Eight drugs (vincristine [VCR], hydroxyurea, procarbazine, CCNU, cisplatin, cytosine arabinoside [Ara-C] high-dose methylprednisolone, and either cyclophosphamide or dacarbazine) were administered within 12 hours in an attempt to minimize myelosuppression. Courses were repeated at 2- to 4-week intervals. The regimen was devised to include lipid and water soluble drugs, polar and nonpolar agents, phase-specific and cell-cycle independent agents, and antineoplastics with different mechanisms of action. More than 330 courses of the regimen were administered to 107 children with brain tumors whose tumor had recurred or had been incompletely resected at diagnosis. Tumor response according to protocol-specified criteria and independent review was evaluable in 78% of the patients. After just two cycles of chemotherapy and within a 4- to 6-week interval, 50% had an objective tumor response including 15.5% who had a complete response (CR). Nephrotoxicity and high-frequency hearing losses were noted after three to five courses of therapy in approximately half of the patients. Transfusions with red cells or platelets and use of antibiotics for fever and neutropenia were required in 10% to 25% of patients. The regimen appears satisfactory for preradiation chemotherapy in newly diagnosed patients with residual tumor after surgery, but it must be compared with standard therapeutic approaches in prospective controlled trials before its relative value can be established.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Spiromustine analogues. Relationships between structure, plasma stability, and antitumor activity.

Spiromustine is a hydantoin-containing nitrogen mustard currently in Phase I clinical trial. Since the in vitro plasma half-life of this compound (6.4 min, 37 degrees C, pH 7.4) appeared to be influenced by the hydantoin ring, analogues containing 2-5 methylene spacer groups between this ring and the nitrogen mustard moiety were prepared and evaluated for hydrolytic stability and antitumor activity. Stability correlated with structure and pKa values. The proximity of the hydantoin ring to the mustard function was a stabilizing factor. Activity against murine P-388 leukemia was demonstrated and a gradual decrease in this activity was observed as the hydrolytic instability increased. A relationship between analogue structure and a mass spectral rearrangement ion was identified.

Animals↗
PubMed1986

Nephroblastomatosis and deletion of 11p. The potential etiologic relationship to subsequent Wilms' tumor.

Both nephroblastomatosis and deletions of the short arm of chromosome 11 (11p-) have been associated independently with Wilms' tumor. The finding of 11p- in a specimen of nodular renal blastema in the currently described patient represents a previously unknown association with this chromosomal lesion. The possibility that 11p- produced an abnormal renal substrate (nephroblastomatosis), upon which the action of a second postzygotic genetic alteration led to Wilms' tumor, is considered. It is suggested that, in the present case, tumorigenesis may have been the result of two postzygotic events, one of which may have been postnatal. Recent cytogenetic observations in both Wilms' tumor and retinoblastoma support such an hypothesis.

Child↗
PubMed1985

Nephroblastomatosis and Wilms' tumor. Clinical experience and management of seven patients.

Nephroblastomatosis is an uncommon abnormality believed to represent the persistence of embryonal renal tissue. Its association with simultaneous or eventual Wilms' tumor has led to the speculation that it is a premalignant lesion. The accumulated clinical experience with this process and its progression to Wilms' tumor in three of seven individuals is discussed. It is concluded that conservative tissue sparing surgery, chemotherapy, and ultrasonographic follow-up are the approaches most appropriate for the management of these difficult patients.

Adolescent↗