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Biomedical subjects

G Stoter

Publications and source records attributed to G Stoter.

At least 145 records · Page 8Linked to original sources
PubMed1995

Four cycles of BEP versus an alternating regime of PVB and BEP in patients with poor-prognosis metastatic testicular non-seminoma; a randomised study of the EORTC Genitourinary Tract Cancer Cooperative Group.

We have investigated whether an alternating induction chemotherapy regimen of PVB/BEP is superior to BEP in patients with poor-prognosis testicular non-seminoma. A total of 234 eligible patients were randomised to receive an alternating schedule of PVB/BEP for a total of four cycles or four cycles of BEP. Poor prognosis was defined as any of the following: lymph node metastases larger than 5 cm, lung metastases more than four in number or larger than 2 cm, haematogenic spread outside the lungs, such as in liver and bone, human chorionic gonadotrophin > 10,000 IU l-1 or alphafetoprotein > 1000 IU l-1. The complete response (CR) rates to PVB/BEP and BEP were similar, 76% and 72% respectively (P = 0.58). In addition, there was no significant difference in relapse rate, disease-free and overall survival at an average follow-up of 6 years. The 5-year progression-free and survival rates in both treatment groups were approximately 80%. The PVB/BEP regime was more toxic with regard to bone marrow function; the frequencies of leucocytes below 1000 microliters-1, leucocytopenic fever and platelets below 25,000 microliters-1, throughout four cycles were 28% vs 5% (P < 0.001), 16% vs 5% (P = 0.006), and 10% vs 1% (P = 0.001) respectively. Neuropathy also occurred more often in the PVB/BEP arm: 47% vs 25% (P = 0.001). This study shows that an alternating regimen of PVB/BEP is not superior to BEP and that it is more myelo- and neurotoxic.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Final report of a phase II study of interleukin 2 and interferon alpha in patients with metastatic melanoma.

Fifty-seven patients with metastatic melanoma were treated with interleukin 2 (IL-2) 7.8 MIU m-2 day-1 as a continuous infusion for 4 days combined with interferon alpha (IFN-alpha) 6 MIU m-2 day-1 subcutaneously on days 1 and 4. The cycle was repeated every 2 weeks for a maximum number of 13 cycles. Of the 51 evaluable patients, one (2%) achieved a complete and seven (14%) a partial response (total response rate 16%; CI 7-29%). Median time to progression and median survival were 2.5 and 11.3 months respectively. This regimen of IL-2 and IFN-alpha appeared to be only moderately active.

Adolescent↗
PubMed1995

Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study.

Twenty-three patients with pleural mesothelioma stage I-IIA were entered in a study of continuous daily intrapleural infusion of interleukin 2 (IL-2) for 14 days, repeated every 4 weeks. IL-2 was administered according to a groupwise dose escalation schedule (group A, 3 x 10(4); group B, 3 x 10(5); group C, 3 x 10(6); group D, 6 x 10(6); group E, 18 x 10(6); and group F, 36 x 10(6) IU day-1). Each group consisted of at least three patients. Intrapleural administration of IL-2 was associated with acceptable toxicity. All patients were treated on an outpatient basis except for the patients at dose levels E and F. Dose-limiting toxicity was observed at level F, 36 x 10(6) IU daily, and consisted of catheter infection, fever and flu-like symptoms. Intrapleural IL-2 levels were high (> 20,000 IU ml-1) at levels E and F, while serum levels in most patients were not or barely detectable (< 3-30 IU ml-1). Intrapleural IL-2 levels were up to 6000-fold higher than systemic levels. Intrapleural tumour necrosis factor alpha (TNF-alpha) levels varied greatly and did not correlate with IL-2 dosage. Intrapleural mononuclear cells (MNCs) displayed IL-2-induced lymphokine-activated killer (LAK) activity in all patients. Two patients were not evaluable for response owing to catheter-related problems which precluded the delivery of IL-2. Partial response (PR) occurred in 4 of 21 evaluable patients (19%; 95% confidence interval 5-42%) with a median time to progression of 12 months (range 5-37). Stable disease (SD) occurred in seven patients with a median time to progression of 5 months (range 2-7). There were no complete responses (CRs). The median overall survival was 15.6 months (range 3.0-43). No relationship between the dose of IL-2 and response rate was observed. We conclude that IL-2 given intrapleurally is accompanied with acceptable toxicity and has anti-tumour activity against mesothelioma. In view of the refractory nature of the disease IL-2 may be a treatment option for mesothelioma. A formal phase II study is warranted. Based on the observed toxicity, the lack of dose-response relationship and the immunomodulatory effects seen at relatively low-dose IL-2, the recommended dose for a phase II study is 3 x 10(6) IU day-1 using the present treatment schedule.

Aged↗
PubMed1995

Phase I study of weekly high-dose cisplatin combined with long-term oral etoposide in advanced solid tumors.

BACKGROUND: In a previous phase I study we showed that single-agent cisplatin can be given weekly for six weeks at a dose of 80 mg/m2/wk. It has been suggested that etoposide has synergistic activity with cisplatin and the drug can be given orally continuously. We therefore performed a phase I study with weekly cisplatin combined with oral etoposide. PATIENTS AND METHODS: Nineteen patients with metastases of a solid tumor were entered in the study. Cisplatin was administered in hypertonic saline (NaCl 3%). Etoposide was administered as 50-mg capsules. RESULTS: The starting dose was cisplatin weekly at a dose of 70 mg/m2 for six weeks combined with daily oral etoposide at a dose of 50 mg. At the maximum tolerable dose of cisplatin 75 mg/m2/wk and etoposide 50 mg/m2 daily, leukocytopenia and thrombocytopenia were dose-limiting toxic effects which resulted in frequent treatment delays. Other toxicities were mild. Finally, a dose of cisplatin 70 mg/m2/wk weeks 1-2-3 and weeks 5-6-7 in combination with etoposide 50 mg orally days 1-15 and days 29-43 combined a high median cisplatin dose intensity of 52.5 mg/m2/wk with a good patient tolerance. CONCLUSION: It is feasible to administer frequently dosed cisplatin in combination with oral etoposide. Leukocytopenia and thrombocytopenia are dose-limiting toxicities. The schedule will be explored further in phase II studies.

Administration, Oral↗
PubMed1995

Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in pleural mesothelioma.

BACKGROUND: In a previous phase II study with a dose-intensive weekly cisplatin schedule for six cycles, we observed a partial response in 5 of 14 patients with pleural mesothelioma. However, response duration was short (median 6 months). Since oral etoposide may theoretically be synergistic to cisplatin, we performed a phase II study with the combination of both drugs. PATIENTS AND METHODS: Twenty-five chemo-naive patients with pleural mesothelioma were treated with cisplatin 70 mg/m2 days 1-8-15 and days 29-36-43 in combination with oral etoposide 50 mg days 1-15 and days 29-43. Patients with stable disease, or better, continued treatment with oral etoposide 50 mg/m2/day days 1-21 every 28 days RESULTS All patients were evaluable for response and toxicity. Complete response was observed in one patient and partial responses in 5 patients (RR% 24%; 95% Cl: 10%-45%) for a median duration of 30 weeks. Twelve patients had stable disease. The response status never improved during maintenance treatment with oral etoposide. Most patients tolerated the regimen very well. Toxicity was manly haematologic with leukocytopenia causing treatment delays in 8 patients. Ototoxicity grade 1 or 2 was observed in 8 patients, neurotoxicity grade 1 in 9 patients and nephrotoxicity grade 1 in 1 patient. CONCLUSION: Frequently administered cisplatin in combination with oral etoposide has a moderate but definite activity in pleural mesothelioma.

Administration, Oral↗
PubMed1995

Simple prognostic model to predict survival in patients with undifferentiated carcinoma of unknown primary site.

PURPOSE: We performed this study to identify prognostic factors in a subgroup of patients with carcinoma of unknown primary site treated with cisplatin combination chemotherapy. PATIENTS AND METHODS: Seventy-nine patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma of unknown primary site were treated on two consecutive phase II chemotherapy protocols. The first protocol consisted of treatment with 3-week courses of cisplatin, etoposide, and bleomycin (BEP). In the second protocol, cisplatin was administered weekly combined with oral administration of etoposide (DDP/VP). To identify prognostic factors, univariate and multivariate analyses were conducted. RESULTS: In the univariate analysis, performance status, histology, liver or bone metastases, and serum levels of alkaline phosphatase and AST were significant variables to predict survival. In the multivariate analysis, performance status and alkaline phosphatase were the most important prognostic factors. CONCLUSION: Good-prognosis patients had a performance score of 0 (World Health Organization [WHO]) and an alkaline phosphatase serum level less than 1.25 times the upper limit of normal (N). These patients had a median survival duration greater than 4 years. Intermediate-prognosis patients were characterized by either a WHO performance status < or = 1 or an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of 10 months and a 4-year survival rate of only 15%. The poor-prognosis group had both a WHO performance status > or = 1 and an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of only 4 months and none survived beyond 14 months. Treatment strategies for these three groups are discussed. It is suggested that this prognostic model be validated in other patients series.

Adenocarcinoma↗
PubMed1994

Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon. An unexpectedly frequent complication.

BACKGROUND: In a group of patients with metastatic melanoma treated with high dose immunotherapy, there was an unexpectedly high incidence of severe cardiac adverse effects. METHODS: Sixteen patients with metastatic melanoma were treated with high dose interleukin-2 (IL-2) and alpha-interferon (alpha-IFN). Each treatment cycle consisted of IL-2 at a dose of 12 MIU/m2 and alpha-IFN at a dose of 3 MIU/m2, given as intravenous bolus injections every 8 hours on Days 1-5, every 3 weeks for a total of three cycles. Before treatment, careful cardiologic screening was performed, including electrocardiogram (ECG), stress test, cardiac multiple uptake-gated acquisition (MUGA) scan, and echocardiography. During therapy, patients were monitored with daily ECG and creatine phosphokinase measurements. Once cardiac damage was suspected, IL-2 and alpha-IFN were discontinued, and echocardiography, stress test and MUGA-scan were repeated. If indicated, cardiac catheterization with endomyocardial biopsies was performed. RESULTS: Despite pretreatment cardiac screening, seven patients (44%) exhibited myocardial injury. Acute myocardial infarction occurred in one patient, cardiomyopathy developed in four, asymptomatic ECG changes appeared in one, and 1 patient died of acute cardiac arrest. Echocardiography showed hypokinesis and decreased left ventricular ejection fraction. These abnormalities disappeared within 6 months. Cardiac catheterization in four affected patients revealed normal coronary arteries, but endomyocardial biopsies showed interstitial edema, vacuolation, and degeneration of myocytes. Electron-microscopic examination showed fragmentation of myofibrils, swelling of mitochondria and loss of mitochondrial cristae. CONCLUSIONS: This intensive treatment schedule of IL-2 and alpha-IFN is prohibited by severe and life-threatening cardiac toxicity.

Adult↗
PubMed1994

Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09.

BACKGROUND: A novel bioreductive alkylating indoloquinone compound, E09 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)- prop-F128b-en-alpha-ol], has been shown to have distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, but no notable bone marrow toxicity in preclinical models. PURPOSE: A phase I study was carried out to determine the toxicity, maximum tolerated dose (MTD), pharmacology, and antitumor response of E09. METHODS: E09 was administered as a 5-minute intravenous infusion once every 3 weeks to 32 patients with solid tumors. The starting dose of 2.7 mg/m2 was one tenth of the mouse equivalent of lethal dose to 10% of animals (MELD10). Dose was escalated by 100% until the area under the curve (AUC) at the MELD10 was reached, following a Fibonacci-like schedule. The pharmacokinetics of E09 and its metabolite E05A with an open aziridine ring was determined using a new high-pressure liquid chromatographic method and noncompartmental calculation of kinetic parameters. The sigmoid Emax model was used to fit pharmacokinetic parameters to toxicity. The renal function and proteinuria were quantitated and were further evaluated by determining renal clearance ratios of immunoglobulin G (IgG) to albumin and pancreatic amylase to salivary amylase. RESULTS: The 32 patients were treated with a total of 85 assessable courses of E09. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. All symptoms were reversible on day 15 except in two patients, who developed acute renal failure. The ratios of IgG to albumin and pancreatic amylase to salivary amylase suggested a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The pharmacokinetics of E09 showed its rapid elimination from the central compartment but with wide interpatient variation in the overall disposition of the drug. Total plasma clearance of E09 ranged from 3.2 to 24 L/min. The AUC of E09 was linearly related to the administered dose. The relationship between the AUC and proteinuria was best fitted by the sigmoid Emax model (r = .98). In two patients with adenocarcinoma of unknown primary site and in a third patient with bile duct cancer, a partial response was observed. CONCLUSIONS: The MTD of E09 was determined to be 27 mg/m2. The standard approach of drug administration is considered unsuitable because of potential renal toxicity and wide variability in the pharmacokinetics of E09. Individual dose adjustments based on plasma concentration measurements are recommended to combine maximally achievable exposure with tolerable toxicity.

Adult↗
PubMed1994

Increases in leucocyte and platelet counts induced by the alkyl phospholipid hexadecylphosphocholine.

Hexadecylphosphocholine (HePC) is a new alkyl phospholipid that has been shown to have antitumour activity in vitro and in vivo. In vivo studies have shown absence of bone marrow toxicity at therapeutic doses. In addition, at the highest dosage group in rats, an increase in white blood cell counts (WBC) was observed. To study the presence of a similar phenomenon in man, frequent measurements of haematological parameters were performed in a series of phase II studies. 70 patients were treated with daily doses of 100-200 mg of the oral formulation of HePC. WBC and platelet counts were performed weekly. In a subgroup of 23 patients serum levels of haemopoietic growth factors were measured before and during treatment. A significant increase in WBC and platelet counts was seen in 74 and 73% of the patients, respectively. In 4 patients, bone marrow showed normal cellularity, and in 1 patient, bone marrow culture showed normal numbers and sizes of colony forming units. No abnormal levels or trends over time of cytokines were observed. We conclude that oral HePC induces an increase in WBC and platelet counts in the majority of those treated.

Administration, Oral↗
PubMed1994

Predictors of residual mass histology following chemotherapy for metastatic non-seminomatous testicular cancer: a quantitative overview of 996 resections.

Following chemotherapy for metastatic non-seminomatous testicular cancer, surgical resection may demonstrate that residual masses contain purely benign tissue (necrosis), or potentially malignant tissues (histologically viable cancer cells or mature teratoma). The morbidity, mortality and costs of resection demand that resection is based on empirical data rather than on subjective judgements. We reviewed 996 resections from 19 studies to quantify predictors of the histology at resection. Predictors were analysed for each study and combined in a pooled odds ratio (OR). Predictors of necrosis were: (1) a teratoma-negative primary tumour (OR = 5.1); (2) normal tumour markers before chemotherapy [alpha-fetoprotein (AFP): OR = 2.8; human chorionic gonadotrophin (HCG): OR = 1.9; both AFP and HCG: OR = 5.7]; (3) a smaller postchemotherapy abdominal mass (e.g. < or = 20 mm: OR = 3.7); (4) a large shrinkage (> or = 90%: OR = 3.1); (5) lung resections versus abdominal resections (OR = 1.7). Cancer was found in only 4% of residual retroperitoneal masses < or = 20 mm. Further research may combine the primary tumour histology, marker level and mass size to improve clinical guidelines, which define subgroups of patients for whom the benefits of resection do not outweigh the risks.

Biomarkers, Tumor↗
PubMed1994

Pharmacokinetic-dynamic relationship of cisplatin in vitro: simulation of an i.v. bolus and 3 h and 20 h infusion.

The profiles of an i.v. bolus and 3 h and 20 h infusion of cisplatin (CDDP) were simulated in vitro by using a culture of the IGROV1 human ovarian cancer cell line. Disappearance of pharmacologically active unbound CDDP was accomplished by adding human albumin to the medium. Total and unbound CDDP and CDDP-DNA adduct levels were quantitated by atomic absorption spectroscopy (AAS), and tumour cell survival was measured by the clonogenic assay. The design of the experiment resulted in non-significant differences in the magnitude of the area under the concentration-time curve (AUC) of unbound CDDP between the three dose-input functions (AUC i.v. bolus, 6.34 +/- 0.36; 3 h infusion, 6.35 +/- 0.59; and 20 h infusion, 6.76 +/- 0.40 micrograms h ml-1). Also, the differences between the area under the CDDP-DNA adduct-time curves (AUA) of the three dose-input functions were not significant. The initial rate of decline of the CDDP-DNA adduct-time curve was significantly higher for the i.v. bolus and 3 h infusion than for the 20 h infusion. There was a log-linear relationship between the AUC of unbound CDDP and cell survival. These relationships were not significantly different between the three dose-input functions. Variation in the rate of input of CDDP leads to differences in the shape of the AUC and AUA without significant effects on cell survival.

Adenocarcinoma↗
PubMed1994

Weekly high-dose cisplatin in malignant pleural mesothelioma.

BACKGROUND: Cisplatin at conventional doses has marginal activity in mesothelioma. A dose-response relation for cisplatin has been suggested in other tumor types. In a phase I study on weekly cisplatin administration, 3 of 5 patients with mesothelioma responded. Therefore, a phase II study with weekly cisplatin was started with the recommended dose of 80 mg/m2/week for six weeks. PATIENTS AND METHODS: Fourteen patients with mesothelioma stage II, with measurable lesions, were treated with cisplatin at a dose of 80 mg/m2 weekly for six weeks. Cisplatin was administered in 3% NaCl and combined with ondansetron as antiemetic. RESULTS: Five patients had partial responses (response rate 36%; 95% confidence interval 12%-65%) lasting 2-8 months. Seven patients had stable disease. Ototoxicity, grade 2 in 3 patients and grade 3 in 2, was the most troublesome side effect. CONCLUSIONS: Cisplatin given at a higher dose intensity than in conventional schedules is active in mesothelioma. The response duration is short, however, possibly due to lack of effective maintenance therapy.

Adult↗
PubMed1994

Phase II study of prolonged oral etoposide in patients with ovarian cancer refractory to or relapsing within 12 months after platinum-containing chemotherapy.

PATIENTS AND METHODS: Twenty-eight patients with ovarian cancer refractory to or relapsing within 12 months after cisplatin-containing chemotherapy were treated with etoposide 50 mg/m2 daily for 21 days, followed by a 7-day break. RESULTS: Of 25 evaluable patients, 4 achieved partial responses (16%, 95% confidence interval 5%-36%) of 4, 4, 7, and 10 months' duration. The platinum treatment-free intervals for these patients were 2, 9, 7, and 10 months, respectively. Etoposide in this schedule was generally well tolerated, with myelosuppression as the major toxicity, resulting in a median dose intensity over all cycles of 83% (range 47%-100%). CONCLUSIONS: Prolonged oral etoposide is moderately active both in relapsed and platinum-refractory ovarian cancer, and a schedule of 50 mg/m2 days 1-21, every 4 weeks is fairly well tolerated in this usually heavily pretreated and elderly patient population.

Administration, Oral↗
PubMed1994

High expression of the multidrug resistance-associated protein (MRP) in chronic and prolymphocytic leukaemia.

The expression of the multidrug resistance-associated protein (MRP), a new glycoprotein involved in drug resistance, was investigated in tumour samples from 80 patients with chronic B-cell malignancies by a quantitative RNase protection assay. In B-cell chronic lymphocytic leukaemia (B-CLL) (n = 32), either treated (n = 18) or untreated (n = 14), a high percentage of patients (20/32: 63%) had relatively high expression levels of the MRP gene (25U or more). In addition, hyperexpression of the MRP gene was demonstrated in 4/10 (40%) untreated patients with B-cell prolymphocytic leukaemia (B-PLL). In contrast, low MRP mRNA expression levels were detected in hairy cell leukaemia (n = 7), non-Hodgkin's lymphoma (n = 13) and multiple myeloma (n = 18). Statistical analysis of MRP expression in untreated CLL (mean +/- SD 29.2 +/- 18.5 U) versus treated CLL (mean +/- SD 26.7 +/- 13.7 U) did not show significant differences in MRP expression between the two groups. Southern blot analysis did not reveal amplification of the MRP gene in the leukaemia samples with elevated MRP mRNA levels. We conclude that B-PLL and B-CLL frequently display high MRP expression and that this hyperexpression is probably due to transcriptional activation and/or increased mRNA stability.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Expression of the multidrug resistance-associated protein (MRP) in acute and chronic leukemias.

We determined the expression of the multidrug resistance-associated protein (MRP), a new putative transmembrane drug transporter, in peripheral blood cells from healthy volunteers as well as from 60 patients with acute or chronic leukemia, using an RNase protection assay. MRP appeared to be ubiquitously expressed at low levels in all nonmalignant hemopoietic cell types, reflecting its basal constitutive expression. In acute myelocytic leukemia (AML) (n = 16), one of nine untreated patients and two of seven patients with prior chemotherapy showed significant hyperexpression of MRP. In chronic lymphocytic leukemia (CLL) (n = 21), either treated (n = 8) or untreated (n = 13), a high percentage (15 of 21: 71% had relatively high expression levels of the MRP gene. In contrast, low MRP expression levels were detected in acute lymphocytic leukemia (n = 14), and in chronic myelocytic leukemia (n = 9). DNA analysis by Southern blotting did not reveal amplification of the MRP gene in the leukemia samples, including those with elevated MRP mRNA levels. We conclude that relatively high expression of MRP is occasionally observed in AML and at high frequency in CLL, irrespective of treatment, probably due to transcriptional activation and/or increased mRNA stability.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Sensitive isocratic high-performance liquid chromatographic determination of a novel indoloquinone cytotoxic drug (EO9) in human plasma and urine.

A reversed-phase isocratic high-performance liquid chromatographic method is described for the simultaneous determination of EO9, 3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)prop-beta- en-alpha-ol (I), and its ring-opened aziridine analogue EO5A (II), employing ultraviolet detection. Solid-phase sample extraction was used without addition of an internal standard. Plots of peak heights and areas of I and II were linear in the range 5-10,000 ng/ml. The lower limit of detection of both I and II in plasma was 2 ng/ml. The between-day variation of I was 13.9% at 5 ng/ml and lower than 6.2% for concentrations > or = 10 ng/ml. The between-day variation of II at 5 ng/ml was 13.8% and lower than 4.5% for concentrations > or = 10 ng/ml. The assay was developed to enable pharmacological guiding of a phase I study of I in solid tumour cancer patients.

Antineoplastic Agents↗