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Biomedical subjects

E D Kreuser

Publications and source records attributed to E D Kreuser.

At least 55 records · Page 3Linked to original sources
PubMed1994

Weekly therapy with folinic acid (FA) and high-dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma. A multicenter study by the Association of Medical Oncology of the German Cancer Society (AIO).

BACKGROUND: No effective salvage therapy is known for patients with metastatic colorectal carcinoma progressive after chemotherapy with 5-fluorouracil (5-FU)/folinic acid (FA) or 5-FU/alpha interferon (IFN) combinations. The aim of the study was to test whether weekly FA/high-dose 5-FU is an effective therapy in pretreated patients with progressive metastatic colorectal carcinoma. PATIENTS AND METHODS: Between January and December 1992, 57 patients with metastatic colorectal carcinoma were treated with weekly infusions of high-dose 5-fluorouracil (5-FU) (2600 mg/m2 as 24-hour infusion) and folinic acid (FA) (500 mg/m2 as 1-hour infusion prior to 5-FU). All patients were pretreated with chemotherapy, most of them with regimens containing 5-FU i.v. bolus/FA or 5-FU/alfa interferon (IFN), and all had documented progressive disease at the time of entering the study. In patients with partial remission (PR) or stable disease (SD) with improvement of their clinical condition, therapy was continued until progressive disease (PD) was documented. In all other patients therapy was stopped after one course (6 infusions). RESULTS: 5/57 patients (9%) achieved PR, 32/57 (56%) SD, in 19/57 (33%) disease was progressive and one toxic death occurred. 26/32 patients (81%) with SD or PR after the first chemotherapy again obtained SD or PR on high-dose 5-FU/FA but only 8/18 (44%) of those with PD after first chemotherapy did so. The median duration of SD/PR was 3 months and the median survival for all patients 8 months (range 3-17+). Apart from one toxic death, toxicity consisting for the most part of mucositis (n = 24), nausea (n = 23), diarrhoea (n = 18) and hand-foot syndrome (n = 12) was moderate. CONCLUSION: Pretreated patients with metastatic colorectal carcinoma, notably those with a primary PR or SD, can probably benefit from weekly high-dose 5-FU/FA.

Adult↗
PubMed1994

Combination of mitoxantrone and etoposide in the treatment of myelodysplastic syndromes transformed into acute myeloid leukemia.

Mitoxantrone and etoposide have both been shown to be effective in de novo acute myeloid leukemia. Therefore, the combination of mitoxantrone and etoposide, the NOVE regimen, was examined in the treatment of myelodysplastic syndromes (MDS) transformed into acute myeloid leukemia (AML). Twenty-one previously untreated patients (eight females, thirteen males) with a median age of 56 years (range 28-67 years) were studied. Diagnosis of MDS was made within the range of six months to three years before transformation into AML occurred. The NOVE regimen consisted of mitoxantrone 10 mg/m2 day 1-5, and of etoposide 100 mg/m2 day 1-5. After one single course of therapy eleven patients achieved a complete remission (CR) and three patients a partial remission (PR). Nine patients (six in CR and three in PR) received a second course, and the PR was completed to a CR in one patient. Thus, the overall response rate was 66% (14/21 patients), and the CR rate was 57% (12/21 patients). Median duration of CR was 7 months (range 2-10 months). Median survival was 10 months (range 3-20 months) for complete responders and 3 months (range 1-10 months) for patients who did not achieve a CR. For patients with subsequent CR, median time of granulocytopenia (< 500/microliters) and thrombocytopenia (< 20.000/microliters) was 20 days and 18 days, respectively. In conclusion, the NOVE regimen appears to be effective in AML secondary to MDS. However, strategies for remission maintenance are warranted.

Adult↗
PubMed1993

[Late cardiac toxicity in Hodgkin's disease. A study with pulsed Doppler echocardiography].

49 patients (22 women, 27 men, mean age 43.7 [21-65] years) with Hodgkin's disease were examined by Doppler echocardiography a median of 5.37 (2-10) years after the end of chemotherapy (given according to the COPP/ABVD scheme, with or without mediastinal irradiation) for possible chronic changes in myocardium, pericardium or cardiac valves, as well as for any haemodynamic sequelae. Maximal and integrated early (E, Ei) and late (A, Ai) diastolic flow velocities and their ratio (E/A, Ei/Ai) were measured by pulsed Doppler over the mitral and tricuspid valves. Although on two-dimensional echo 21 patients (42.9%) were found to have valvar thickening, 19 (38.8%) pericardial thickening and 9 (18.4%) a reduced fibre shortening fraction, the Doppler indices were statistically not significantly different from those in 25 controls with normal hearts. These echocardiographic data of functional and morphological parameters indicate that there was no effect on various measurements of diastolic function after chemotherapy with or without mediastinal radiation. In successfully treated patients with Hodgkin's disease the described changes are of minor significance.

Adult↗
PubMed1993

Evaluation of late cardiotoxicity with pulsed Doppler echocardiography in patients treated for Hodgkin's disease.

The impact of valvular, myocardial and pericardial abnormalities on cardiac haemodynamics in patients treated for Hodgkin's disease with COPP/ABVD with and without mediastinal irradiation was determined in 49 patients 2-10 years after induction therapy. Diagnostic procedures to evaluate cardiac function consisted of history, physical examination, exercise bicycle stress test, M-mode two-dimensional and pulsed Doppler echocardiography. No patient reported symptoms related to cardiomyopathy, and only one of the 49 had evidence of coronary heart disease. Pericardial thickening was seen on echocardiograms in 19/49 patients (38.8%), valvular thickening in 21/49 (42.9%), and reduced fractional shortening in 9/49 (18.4%). The Doppler-derived mean E and A (+/- SD) of transmitral flow were 0.75 +/- 0.14 m/s and 0.56 +/- 0.09 m/s, respectively, in patients receiving chemotherapy and 0.81 +/- 0.19 m/s and 0.63 +/- 0.20 m/s in those with additional mediastinal irradiation. There was no statistically significant difference between mean E and A in transmitral flow in patients treated for Hodgkin's disease and control subjects. Furthermore, the transtricuspid and hepatic vein flow velocities did not differ significantly. Although the present study demonstrates high frequencies of pericardial and valvular thickening in patients treated for Hodgkin's disease with the COPP/ABVD regimen with or without mediastinal irradiation, it showed no impact on cardiac flow velocities. The abnormalities might thus be of minor clinical relevance in these patients.

Adult↗
PubMed1993

The role of LHRH-analogues in protecting gonadal functions during chemotherapy and irradiation.

Therapeutic success has focused attention on late effects in patients with testicular cancer, Hodgkin's disease, non-Hodgkin's lymphoma, and acute leukaemia. Since most patients with testicular cancer are young, the impact of cytotoxic chemotherapy on fertility and hormone deficiency has become particularly important. It has been shown that pulsatile secretion of luteinizing hormone releasing hormone (LHRH) is a prerequisite for normal gonadal function. In contrast, non-pulsatile, chronic treatment with supraphysiological doses of LHRH-analogues (LHRHA) results in suppression of the pituitary-gonadal axis. It has been suggested that inhibition of spermatogenesis during exposure to cytotoxic drugs might reduce gonadal toxicity. The protective effects of LHRHA during chemotherapy or irradiation has been examined in 11 preclinical studies. In only 6 out of 11 models could protection be demonstrated. Four clinical trials have been performed using LHRHA as a gonadal protector. In none of these trials could LHRHA significantly influence severity and duration of germ cell impairment. New approaches are needed to minimize or even prevent gonadal toxicity during chemotherapy or irradiation, such as reduction of courses, alternative schedules, or new drugs.

Animals↗
PubMed1992

Recombinant human stem cell factor stimulates growth of a human glioblastoma cell line expressing c-kit protooncogene.

The growth of a panel of eight different human glioblastoma cell lines was examined in a human tumor cloning assay in agar, a tritiated thymidine uptake assay, and by counting cell numbers, in cultures performed in the absence or presence of increasing concentrations (1 to 100 ng/ml) of recombinant human stem cell factor (SCF). Growth of 7 of 8 cell lines was not significantly and reproducibly affected by recombinant human SCF. However, growth of the CRL 1620 cell line could be stimulated up to 5-fold by the cytokine. In contrast to the other cell lines investigated, CRL 1620 expressed the c-kit protooncogene assessed on the mRNA and protein level. Furthermore, SCF-induced proliferation of CRL 1620 cells was sensitive to the tyrosine kinase inhibitor erbstatin. Our data suggest that SCF can be operative in growth modulation of malignant cells outside the hematopoietic system, and this finding should be further studied for its possible clinical implications.

Cell Division↗
PubMed1992

Effect of interleukin-3 and granulocyte-macrophage colony-stimulating factor on growth of xenotransplanted human tumour cell lines in nude mice.

The clonal growth of cell lines from some human solid tumours can be stimulated by haematopoietic growth factors such as recombinant human (rh) interleukin-3 (IL-3) and rh granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Among these cell lines are the human colorectal adenocarcinoma cell line HTB 38 and the human small-cell lung cancer cell line HTB 119. Here we report on a series of experiments studying the influence of subcutaneously administered rhIL-3 and rhGM-CSF on the in vivo growth of HTB 38 and HTB 119 cell lines as xenografts in athymic nu/nu BALB/c mice. Beginning 1 day after transplantation of the tumour the cytokines were administered daily for 20 days as a subcutaneous bolus distant from the tumour lesion at dose levels up to 1 mg/m2/day. The cytokines caused no significant and reproducible growth modulation of the tumours in vivo.

Adenocarcinoma↗
PubMed1992

Long-term gonadal dysfunction and its impact on bone mineralization in patients following COPP/ABVD chemotherapy for Hodgkin's disease.

Only limited data is currently available on long-term gonadal toxicity and its impact on bone mineralization in men and women treated for Hodgkin's disease. The present study was therefore conducted to evaluate gonadal toxicity and bone loss in 49 patients with Hodgkin's disease 2-10 (median 5.37) years after chemotherapy. Most patients were treated with the COPP/ABVD regimen +/- irradiation according to the protocols of the German Hodgkin Study Group. Blood samples were tested for gonadotropins (FSH, LH), gonadal steroids, parathyroid hormone, osteocalcin, and calcitonin. Bone mineral density was measured using single- and dual-energy quantitative computed tomography as well as single-photon absorptiometry. FSH serum levels were significantly increased in 21/27 (80%) men demonstrating germ-cell aplasia. 13/15 (86%) men showed azoospermia after the COPP/ABVD regimen. In contrast, testosterone levels were within normal limits in all men tested, suggesting normal Leydig-cell function. 17/22 (77%) women exhibited increased FSH and LH levels, indicating premature ovarian failure. Women with therapy-induced ovarian failure had a significantly lower trabecular (98 +/- 34) and cortical (292 +/- 48 mg/cm3) spinal bone density than those with normal ovarian function. Men showed no evidence of bone loss after therapy. These data suggest severe gonadal toxicity in both men and women treated with the COPP/ABVD regimen. In female patients, drug-induced ovarian failure has a significant impact on bone mineralization.

Adolescent↗
PubMed1992

[Combination of interferon-alpha with cytostatic drugs: a potentially successful therapeutic approach in metastatic melanoma].

Pharmacological treatment of disseminated melanoma is characterized by rather low objective response rates with mono- and combined chemotherapy and by significant toxicity. For these reasons, many centres do not now offer any systemic treatment to melanoma patients with distant metastases. Systemic treatment with interferons has not fulfilled all that was expected of it, but type-I interferons (-alpha, -beta) have proved to be effective in about 10-15% of patients treated. The antitumour activity of these substances seems to be related mainly to their antiproliferative effect, whereas no immunomodulatory effects have been substantiated in clinical trials. Combined therapy with interferons and cytostatic drugs was introduced into clinical trials only a few years ago, and the initial results are promising. Large studies with a total of over 200 patients have already been performed to evaluate the combination of interferon-alpha and dacarbazine. This treatment was effective in around 50% of the patients, complete or partial remission being achieved in 30% and stabilization of the disease, in 20%. Toxicity is significant, but still manageable; the new generation of antiemetic drugs (serotonin receptor blockers), in particular appears promising. Up to now, no improvement of efficacy has been found following addition of interferon-alpha to cisplatin in four clinical trials. In a study in our own department, however, the combined action of interferon alpha and vindesine was found to be superior to that of either used as a single agent, and the combination was well tolerated on an outpatient basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1992

Combined treatment of metastatic melanoma with interferons and cytotoxic drugs.

The treatment of disseminated melanoma with monotherapy and combined chemotherapy is still associated with rather low objective response rates and significant toxicity. Therefore, more effective substances and regimens with less toxicity are desired in the pharmacologic treatment of metastatic melanoma. The initial high expectations placed in systemic cancer treatment with interferons (IFNs) were not fulfilled, but IFN-alpha as a single substance revealed an objective response rate of 10% to 15% in melanoma patients. Clinical and experimental results suggest that the antitumoral activity of IFNs is mainly related to their antiproliferative effect, whereas immunomodulatory effects were not substantiated in clinical investigations. Results of in vitro trials showed that type-I IFNs may produce antagonistic effects combined with some agents (eg, cisplatin) and synergistic effects combined with others (eg, vindesine and BCNU). Clinical trials with combined IFN and cytostatic drug therapy were started a few years ago and have yielded promising initial results. Several studies with an entire number of more than 200 patients have already been performed to evaluate the combination of IFN-alpha and dacarbazine. This regimen was effective in over 50% of the patients, leading to complete or partial remissions in 27% and stabilization of the disease in an additional 28%. Toxicity is significant but still manageable, especially with a new generation of antiemetic drugs (serotonin receptor blockers). Several clinical trials performed so far did not find an improved efficacy by adding IFN-alpha to cisplatin or to vinblastine. The combination of IFN-alpha and vindesine seems to be more favorable and superior to the response rates of single agents and was well tolerated in an ongoing trial in our clinic. Recently, a new generation of multidrug combinations including IFN-alpha has been initiated and several reports with overall response rates greater than 50% have been published. In conclusion, combined regimens with IFN-alpha and different cytostatic drugs seem to be superior to treatments with cytostatic drugs alone and rather safe in disseminated melanoma. Additional combinations of IFNs and cytostatic drugs should be evaluated in future in vitro studies and in clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Synergistic antitumor interactions between newly synthesized ruthenium complexes and cytokines in human colon carcinoma cell lines.

The purpose of these studies was to assess the antiproliferative properties of newly synthesized, heterocyclic ruthenium complexes alone and in combination with cytokines (tumor necrosis factor-alpha, interferon alfa, beta, and gamma) against various human colon carcinoma cell lines. To determine whether any of these ruthenium compounds possesses antitumor activity and reveals synergistic interaction with cytokines six new ruthenium complexes were studied. All six compounds exerted dose-dependent antitumor effects in all colon cancer cell lines tested. The most effective compounds were trans-indazolium[tetrachloro(2H-indazole)ruthenate (III, N1)] and trans-indazolium[tetrachlorobis(1 H-indazole)ruthenate (III, N2)]. Interferon alfa, beta, and gamma as well as tumor necrosis factor-alpha exerted only minimal antiproliferative effects in colon carcinoma cell lines. The data were further analyzed to determine whether preincubation with cytokines altered sensitivity of the cells to synergistically potentiating growth-inhibitory effects. Although simultaneous incubation of ruthenium complexes and interferon did not result in synergistic or additive interactions, 24-hour preincubation with interferon alfa, beta, and gamma significantly enhanced antitumor activity. We conclude from these data that two of six newly synthesized ruthenium complexes possess antiproliferative activity against a panel of human colon carcinoma cell lines. Moreover, biological modulation with interferon using 24-hour preincubation resulted in synergistic interactions. We are planning a phase I trial, since antitumor activity of these ruthenium compounds has been demonstrated in vitro and in vivo, and toxicity as well as stability data are now available.

Carcinoma↗
PubMed1992

A phase II trial of interferon alpha-2b with folinic acid and 5-fluorouracil administered by 4-hour infusion in metastatic colorectal carcinoma.

Preclinical data suggest that folinic acid as well as interferon alpha-2b may enhance the antitumor activity of 5-fluorouracil (5-FU). In a phase I trial, we recently showed that interferon alpha-2b (IFN), folinic acid and 5-FU can be safely administered with a 4-hour infusion of 5-FU. We therefore initiated a phase II trial evaluating the efficacy and safety of these three drugs. Forty-five evaluable patients with advanced metastatic colorectal cancer, documented progressive disease, and previously unexposed to chemotherapy were treated with sequential IFN 5 MU/d subcutaneously and folinic acid 200 mg/m2/d as bolus on days 1 to 7 followed by 5-FU in a 4-hour infusion at a dose of 500 mg/m2/d, resulting in a total dose of 3,500 mg/m2/course. This schedule was repeated on day 21. A total of 204 courses of therapy were completed. One of 45 patients (2%) achieved a complete response, and 13 of 45 patients (29%) achieved a partial response. An additional 16 patients (36%) had stable disease. The median time to disease progression was seven months (2 to 24 months). Despite the relatively high-dose intensity of 5-FU, toxicity was very mild. Grade 3 or 4 myelosuppression, stomatitis, and nausea/vomiting occurred in only three of 45 patients (7%). Four of 45 patients (9%) suffered from severe (grade 3/4) diarrhea. Neurotoxicity and infections of grade 2 to 4 did not occur. From these data we conclude that modulation of 5-FU with both folinic acid and IFN induces an overall response rate of 31% in disseminated colorectal cancer. Using a 4-hour application schedule of 5-FU, the therapeutic index can be improved even for high-dose intensity and requires further evaluation in combination with other modulators.

Adult↗
PubMed1992

A phase I trial of interferon alpha-2b with folinic acid and 5-fluorouracil administered by 4-hour infusion in metastatic colorectal carcinoma.

Preclinical data suggest that both folinic acid and interferon may enhance the efficacy of 5-fluorouracil (5-FU) in colorectal carcinoma. We therefore initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of the combination of recombinant interferon (IFN) alpha-2b with folinic acid (FA) and 5-FU. Seventeen patients with colorectal cancer who failed local chemotherapy received 5-FU as a 4-hour infusion, preceded by a bolus of FA and IFN. The 5-FU dose was escalated over the range of 400 to 650 mg/m2/d for a period of 7 days. Folinic acid was administered as a bolus in a fixed dose of 200 mg/m2/d and IFN as 5 million U/d subcutaneously on days 1 to 7. A total of 89 courses of therapy were completed for the 17 patients, of which there were 10 paired courses with a combination of 5-FU and IFN or 5-FU alone, being performed to analyze the pharmacokinetics and modulation of 5-FU by IFN. The maximum tolerated dose of 5-FU using this combination and a 4-hour schedule was 600 mg/m2/d for 7 days. The dose-limiting toxicity of this regimen was diarrhea. Mucositis and myelosuppression was not a marked problem at dose levels of 400 and 500 mg/m2/d for 7 days. However, at a dose level of 600 to 650 mg/m2/d for 7 days, grade 3 and 4 (WHO) leukopenia occurred in 50% and mucositis occurred in 33%. At a given dose of 5 million U, IFN did not significantly influence 5-FU serum levels. Mean steady-state serum levels of 5-FU at 500 mg/m2 given as a 4-hour infusion were 16.55 +/- 9.34 mumol/L and 18.23 +/- 12.77 mumol/L with and without IFN, respectively. Mean area under the curve (mumol/L x min) was 4,008 +/- 2,133 and 5,114 +/- 2,567 with and without interferon, respectively. Objective responses were seen in one of 17 of these heavily pretreated patients and stable disease was seen in seven of 17 patients. The recommended dose of 5-FU for use of phase II studies is 500 mg/m2/d for 7 days. We conclude that the toxicity of 5-FU plus FA with and without IFN alpha-2b can be reduced by using a 4-hour infusion instead of a bolus.

Adult↗
PubMed1992

[Pathophysiology, incidence and therapy of malignant pleural effusion].

Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. Effective control of recurrent malignant effusion can greatly improve the quality of life. On the basis of comparison involving, efficacy, toxicity, and costs we recommend intrapleurally tetracycline with chest tube drainage as the technique of choice inducing a response rate of 70%. Instillation of fibrin glue into the thoracic cavity through a tube is also a safe and effective technique and should be employed when tetracycline fails. Mediastinal radiation constitutes the best local therapy secondary to lymphoma. Pleurectomy would be appropriate in a very small subset of patients whose performance status is exceptionally good and whose malignancy ist otherwise under good control.

Antineoplastic Agents↗