Biomedical subjects

T Cerny

Publications and source records attributed to T Cerny.

At least 55 records · Page 3Linked to original sources

PubMed1999

Ifosfamide-induced stomatocytosis and mesna-induced echinocytosis: influence on biorheological properties of blood.

Ifosfamide is an alkylating agent which has poorly understood toxic side effects such as encephalopathy. We hypothesized that ifosfamide and concomitantly applied mesna could have an influence on the flow properties of blood, and thus carried out an in vitro study. Whole blood was incubated in vitro with increasing concentrations of ifosfamide (0-50 mg/ml), mesna (0-20 mg/ml) and combinations thereof. Chloroacetaldehyde, a major metabolite of ifosfamide, was also studied (0-5 mmol/l). Ifosfamide led to a dose-dependent stomatocytic shape transformation and mesna to an echinocytic shape transformation of erythrocytes. These shape changes were reversible upon removal of the causing agent. Both shape changes increased whole blood viscosity. Erythrocyte aggregation was decreased by both drugs at high concentration. Erythrocyte deformability, as measured with the transit time through 5-microm pores, was decreased by mesna and remained unaffected by ifosfamide. These effects were seen at concentrations which may be reached in vivo at the infusion site of the drugs into a vein and in the urinary tract. We conclude that ifosfamide and mesna interact with the lipid bilayer of the cell membrane, which may contribute to the toxicity of the compounds.

Adult↗

PubMed1999

[Quality of life of patients with metastatic breast or intestinal cancer, treated with anthroposophic medicine or with mainstream medicine, the latter with or without psycho-oncologic or supplementary anthroposophic therapy].

This project dealt with two subjects. On the one hand, the measurement of the quality of life of cancer patients which needed to be further refined in order to assess the usefulness and efficacy of a treatment by complementary medicine. On the other hand, it was important to know whether severely ill cancer patients treated in an anthroposophical clinic would differ from equally ill patients in a university hospital in terms of attitude towards their illness and in terms of clinical diagnosis. Finally, an attempt was made to demonstrate an improvement of quality of life in conventionally treated patients of the university hospital, who were offered an additional treatment either with a supportive-expressive group therapy or with an anthroposophical therapy. More than 500 patients participated in the study. There were marked sociodemographic and medical differences between the patients of the anthroposophical clinic and those of the university hospital. In addition, it seems that spiritually oriented and active, problem-oriented coping contribute a lot to the quality of life. It was not possible to truly compare the value of the two additional therapies offered to the patients at the university hospital because patient accrual was much slower than anticipated and many patients left the study too early for health reasons or death.

Ambulatory Care Facilities↗

PubMed1999

T-cell-rich B-cell non-Hodgkin's lymphoma mimicking Hodgkin's disease.

We report on a patient with recurrent T-cell-rich B-cell lymphoma (TCRBCL), initially misdiagnosed as a lymphocyte-rich Hodgkin's disease. This case exemplifies the diagnostic problems of TCRBCL and the need for immunophenotypic analysis to differentiate TCRBCL from Hodgkin's disease, nodular paragranuloma and peripheral T-cell lymphoma. A rather unusual aspect is the long disease-free interval between the excision of the node in and the late relapse in 1996. The significance of the abundant T-cell infiltration in this B-cell neoplasm will be discussed and the concepts concerning antitumor response will be reviewed. Based on epidemiological data and the clinical behaviour TCRBCL does not seem to represent a distinctive pathological entity.

Adult↗

PubMed1998

[2-CDA in treatment of hairy cell leukemia: a comparison between intravenous and subcutaneous administration. Swiss Study Group of Applied Cancer Research].

2-chlorodeoxyadenosine (2-CDA) is very effective in the treatment of patients with hairy-cell leukaemia, with an overall response rate of 80-95%. The standard treatment is a continuous intravenous infusion for 7 days. The bioavailability of 2-CDA after subcutaneous injection is 100%, but the concentration-time profile is completely different compared to continuous intravenous administration. In the present study we compared the intravenous standard treatment (group 1, n = 22; 0.1 mg/kg/d for 7 days, civ.) with subcutaneous administration of 2-CDA (group 2, n = 62; 0.14 mg/kg/d for 5 days, s.c.) in patients with hairy-cell leukaemia. In group 1, 96% (21/22) of patients responded to 2-CDA (complete remission 73%, partial remission 23%) and in the second group 97% were responsive (complete response 76%, 47/62; partial remission 21%, 13/62). The percentage for moderate and severe infections in the trial with intravenous and subcutaneous treatment was 14% and 26% respectively (p = 0.37). We conclude that subcutaneous administration of 2-CDA in patients with hairy-cell leukaemia is feasible and economical and results in comparable responses and toxicity compared to the intravenous standard treatment.

2-Chloroadenosine↗

PubMed1998

Multiple drug resistance parameter expression in ovarian cancer.

OBJECTIVE: Drug resistance represents a complex problem for the treatment of ovarian cancer. This study was undertaken to assess several putative resistance parameters (DRP) in parallel in cancer tissue from newly diagnosed patients with ovarian cancer in order to establish possible correlations to known clinical factors and prognosis. MATERIAL AND METHODS: Tumor and adjacent tumor free ovarian tissue samples from 39 consecutive, untreated female patients with ovarian cancer were obtained and as potential DRPs, the level of glutathione (GSH), the activities of glutathione S-transferase (GST), glutathione-peroxidase (GPx), O6-alkylguanine-DNA alkyltransferase (Atase), and topoisomerase II (TOPO) were assessed biochemically, and P-glycoprotein (Pgp) was assessed by Western blotting. RESULTS: Interindividual variations were high and each patient exhibited an individual profile of resistance factor expression. Levels of GSH were increased with stage (linear trend: P < 0.002), and GST, GPx, and Atase showed a similar tendency. With few exceptions no correlation was found between the DRPs and other prognostic characteristics. All tested DRPs except Pgp showed significantly higher levels/activities in tumor tissues than in the surrounding tumor free tissues (P < 0.05). The tested DRPs were found not to influence response to treatment. CONCLUSIONS: It is concluded that elevated DRPs reflect an intrinsic pattern of components of the detoxifying system in the tumor tissue. This pattern differs between patients and may partly explain the difficulty to assess the clinical importance of individual DRPs in order to translate them into recommendations for specific therapies.

Adult↗

PubMed1998

Isolated lung perfusion: single-pass system versus recirculating blood perfusion in pigs.

BACKGROUND: Cytostatic isolated lung perfusion has been advocated for treating pulmonary metastasis of soft tissue sarcoma. Different techniques of isolated lung perfusion have been developed. METHODS: Isolated lung perfusion with and without doxorubicin was performed on white pigs during 15 minutes either by a single-pass system (n = 7) or by a recirculating-blood perfusion system (n = 7). Three animals with endovenous drug application served as controls. Leakage was assessed using isotopic tracers. Perfusion-induced lung tissue injury was determined by postperfusion chest radiographs, by angiotensin-converting enzyme-to-protein ratio in the plasma and in the bronchioalveolar lavage fluid, and by wet-to-dry weight ratio and histologic examination of lung biopsy specimens at 20 and 50 minutes. Doxorubicin concentration in lung tissue and plasma was compared between the three study groups. RESULTS: All isolated lung perfusion studies were successfully performed without significant systemic leakage (< 0.6%). Wet-to-dry weight ratio was significantly lower after single-pass as compared with recirculating-blood perfusion and endovenous drug application at both time points (5.0 +/- 1.1 and 5.3 +/- 0.8 for single-pass versus 6.6 +/- 1.1 and 6.9 +/- 0.5 for recirculating-blood versus 6.6 +/- 0.2 and 5.9 +/- 0.7 for the control group, respectively; p < 0.05). Angiotensin-converting enzyme-to-protein plasma ratio in the single-pass group was significantly lower only at 20 minutes (6.3 +/- 2.4 versus 9.3 +/- 1.0 versus 9.7 +/- 1.9, respectively; p < 0.05) but not at 50 minutes. Angiotensin-converting enzyme-to-protein ratio in bronchoalveolar lavage fluid, histology of lung biopsy specimens, and chest radiographs did not differ significantly between the three groups. Doxorubicin lung tissue concentration was not significantly different after single-pass (17.5 micrograms/g) and recirculating-blood perfusion (21.9 micrograms/g), but was significantly higher than after endovenous drug application (3.0 micrograms/g; p < 0.01). CONCLUSIONS: Both isolated lung perfusion techniques resulted in a sixfold to sevenfold higher doxorubicin lung tissue concentration than after endovenous application. Isolated lung perfusion-induced lung injury was similar for both techniques, but recirculating-blood perfusion appeared to result in more acute lung injury and was technically more demanding than single-pass perfusion.

Animals↗

PubMed1998

Reduced dose of subcutaneous cladribine induces identical response rates but decreased toxicity in pretreated chronic lymphocytic leukaemia. Swiss Group for Clinical Cancer Research (SAKK).

PURPOSE: To study the efficacy and the safety of cladribine (2-chlorodeoxyadenosine, 2-CDA) administered as 24-hour infusions or as subcutaneous bolus injections at two different doses to patients with relapsing or refractory chronic lymphocytic leukaemia (CLL). PATIENTS AND METHODS: In this non randomised 2-cohort study, 20 patients with pretreated CLL received cladribine at a dose of 0.7 mg/kg/cycle as continuous i.v. infusions over seven days (group 1) and 35 patients were treated at a reduced dose of 0.5 mg/kg/cycle given as s.c. bolus injections for five days (group 2). After two cycles of four week duration, response was assessed. In the case of progressive disease, therapy was discontinued, otherwise a maximum of four additional cycles were administered until best response. RESULTS: A total of 130 cycles were administered (group 1: 41, group 2: 89). Patient characteristics in both groups were comparable. The median dose intensities were 0.172 mg/kg per week and 0.123 mg/kg per week for groups 1 and 2, respectively (P < or = 0.0001). The overall response rate for all 55 patients was 38% (95% confidence interval (95% CI): 25%-52%), with 5% CR and 33% PR. Response was similar in both patient groups (35% in group 1, 40% in group 2). No association between cladribine dose intensity and response rate was found, and there was no difference between patients relapsing after or refractory to previous therapies (11 of 24 vs. 10 of 31). Median remission duration was six months in both groups. Toxicity, in particular infections (all WHO grades, 34% in group 1 versus 7% in group 2) and myelosuppression (grade 1-4 neutropenia, 72% versus 41% of cladribine cycles) were statistically significantly more frequent in group 1. CONCLUSION: Cladribine is active in heavily pretreated patients with chronic lymphocytic leukaemias. Dose reduction by 29% led to similar response and remission duration, but to a significant decrease of myelotoxicity and risk of infection. Cladribine administered as s.c. bolus injections at 0.5 mg/kg per cycle is safe and this dose level should not be exceeded in this patient population.

Adult↗

PubMed1998

Primary cervical malignant teratoma with a rib metastasis in an adult: five-year survival after surgery and chemotherapy. A case report with a review of the literature.

We report a case of a man presenting with a cervical malignant teratoma and a chondrosarcomatous rib metastasis. He was alive and free of recurrence five years and 10 months (= 70 months) after resection of the primary mass, followed by chemotherapy and subsequent resection of the rib tumor. This is the 35th patient reported in the literature and the first description in which an 'adjuvant' or primary chemotherapy was used. Previous patients with a cervical malignant teratoma, reported after lethal outcome, had survivals of one to 22 months (median nine months). In all patients with a preoperative clinical impression of an aggressive, differentiated or undifferentiated malignancy, the definite diagnosis of teratoma could only be made histologically. By analogy to germ cell tumors, the prognosis of malignant teratoma might be improved if complete excision is combined with new, adjuvant chemotherapy protocols for germ cell tumors. Lessons learned from this case are placed in the context of germ cell tumors in general and of non-gonadal malignant teratomas in particular.

Adult↗

PubMed1998

The cognitive-spiritual dimension--an important addition to the assessment of quality of life: validation of a questionnaire (SELT-M) in patients with advanced cancer.

UNLABELLED: Questions of meaning and challenge by illness, i.e., the spiritual dimension of quality of life (QL) traditionally played an important role in anthroposophically oriented medicine and have gained importance in palliative medicine and supportive care. In the context of a research project on QL in patients with advanced cancer, we therefore investigated the psychometric properties of a questionnaire covering spiritual QL issues, with the aim of providing a module for the assessment of cognitive-spiritual QL. PATIENTS AND METHODS: We investigated 89 patients with advanced breast and gastro-intestinal cancer. Construct validity of a modified version of the SELT (Skalen zur Erfassung von Lebensqualität bei Tumorkranken), the SELT-M was tested by multitrait scaling analysis. Discriminant and convergent validity were also tested. The EORTC QLQ-C30 was used as a standard for validation. Results showed the SELT-M as feasible in administration. Four of the five SELT-M subscales were internally consistent (Cronbach's Alpha = > 0.7). The subscale on spiritual QL showed higher within than outside subscale correlations for six of its eight items. Association of the SELT-M with the EORTC QLQ-C30 was good for the items and subscales covering the same aspects of QL in both questionnaires: emotional (Spearman r = 0.61), physical functioning (r = -0.54) and fatigue (r = -0.75). In accordance with expectations, there was no association between spiritual QL with any EORTC QLQ-C30 subscales. Self-assessed spiritual QL in the SELT-M corresponded well with interviewer assessments (test for trend accross ordered groups, P = 0.0023). CONCLUSIONS: Overall there is confirming evidence for the hypothesised structure of the SELT-M, especially for the newly developed module on spiritual QL. This module may be used as a module together with other cancer specific QL questionnaires.

Breast Neoplasms↗

PubMed1998

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK).

UNLABELLED: Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. PATIENTS AND METHODS: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. RESULTS: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. CONCLUSIONS: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival.

Adolescent↗

PubMed1998

Ventricular arrhythmia and torsade de pointe: dose limiting toxicities of the MDR-modulator S9788 in a phase I trial.

BACKGROUND: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. PATIENTS AND METHODS: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined. RESULTS: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. CONCLUSIONS: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase 1 trials of S9788 infused over six hours precluded the further clinical development of S9788.

Adult↗

PubMed1998

Fewer infections, but maintained antitumor activity with lower-dose versus standard-dose cladribine in pretreated low-grade non-Hodgkin's lymphoma.

PURPOSE: To study the efficacy and the safety of cladribine (2-chlorodeoxyadenosine [2-CDA]) administered at two different dosages. PATIENTS AND METHODS: In this two-cohort study, patients with low-grade refractory/relapsing non-Hodgkin's lymphoma (NHL) received 2-CDA at a dose of 0.7 mg/kg per cycle as a continuous intravenous (i.v.) infusion (group 1, n = 44) or at a reduced dose of 0.5 mg/kg per cycle as a subcutaneous (s.c.) bolus injection (group 2, n = 60). Three 2-CDA cycles at > or = 4-week intervals were planned, then treatment could be pursued until six cycles. RESULTS: A total of 300 cycles were administered (group 1, 114 cycles; group 2, 186). Patient characteristics in both groups were comparable. The median dose-intensities were 0.17 mg/kg/wk and 0.13 mg/kg/wk for groups 1 and 2, respectively (P < or = .0001). The overall response rate for all 104 patients was 54% (95% confidence interval [CI], 45% to 66%; 15% complete response [CR] and 39% partial response [PR]). Response was similar in both patient groups (57% in group 1 and 53% in group 2; P = .72), and no association between 2-CDA dose-intensity and response rate was found (P = .35). Median remission duration was 7 and 12 months in groups 1 and 2, respectively (P = .21). Toxicity, in particular opportunistic infections (> or = grade 2, 30% in group 1 v 7% in group 2; P = .003) and myelosuppression (> or = grade 3 neutropenia, 33% v 8% of 2-CDA cycles, P < .0001), were more frequent in group 1. Multiple logistic regression analysis showed that the infection risk (grade > or = 2) was decreased by 81% with 2-CDA dose reduction in group 2 after adjusting for number of pretreatment regimens and time since diagnosis (P = .01). CONCLUSION: When administered as a s.c. bolus injection, 2-CDA at 0.5 mg/kg per cycle is safe and this dose level should not be exceeded in this patient population.

Adult↗

PubMed1998

Thiodiglycolic acid is excreted by humans receiving ifosfamide and inhibits mitochondrial function in rats.

Thiodiglycolic acid has been identified as a major metabolite of the anticancer drug ifosfamide in humans. Patients treated with 12-16 g ifosfamide/m2.day excreted thiodiglycolic acid ranging from 0.10 +/- 0.02 mmol on the first day of therapy, to a maximum of 3.27 +/- 0.15 mmol on the fourth day of ifosfamide infusion. This amounted to 5.4 +/- 0.2% of the administered dose of ifosfamide appearing as thiodiglycolic acid in urine during a 5 days' continuous ifosfamide infusion. Thiodiglycolic acid (50mg/kg) administered to rats inhibited the carnitine-dependent oxidation of [1-14C]palmitic acid by 55%, but affected neither the oxidation of [1-14C]octanoic acid, which is carnitine-independent, nor the oxidation of [1, 4-14C]succinic acid, a marker of Kreb's cycle activity. Additionally, thiodiglycolic acid (30 microM) inhibited oxidation of palmitic acid but not palmitoyl-L-carnitine in isolated rat liver mitochondria, indicating that it either sequesters carnitine or inhibits carnitine palmitoyltransferase I. This study elucidates a specific mitochondrial dysfunction induced by thiodiglycolic acid which may contribute to the adverse effects associated with ifosfamide chemotherapy.

Animals↗

PubMed1998

[Is preoperative chemotherapy in locally advanced non-small-cell bronchial carcinoma of value?].

Although surgeons are able to resect completely locally advanced non-small cell lung cancer with mediastinal lymph node involvement (stage IIIA), the majority of patients succumb from metastatic disease. Therefore, neoadjuvant therapy was introduced in the management of this disease in order to eradicate distant metastases at an early stage. Phase II trials with preoperative chemotherapy in stage IIIA patients have shown that the pathological response (amount of tumour necrosis) and the clearance of mediastinal lymph node correlate with a better survival and is the best predictor for eradication of distant metastases. Indeed, three small randomised phase III studies have demonstrated a survival advantage for preoperative chemotherapy compared to surgery alone. Further studies are required to determine the best neoadjuvant regimen inducing the largest amount of tumour necrosis.

Carcinoma, Non-Small-Cell Lung↗

PubMed1998

Comparative pharmacokinetics of oral and intravenous ifosfamide/mesna/methylene blue therapy.

Oral treatment with ifosfamide results in dose-limiting encephalopathy. Methylene blue is effective in reversal and prophylaxis of this side effect. In the present study, the pharmacokinetics of ifosfamide after iv and po therapy in combination with prophylactic administration of methylene blue were investigated. Nine patients with metastatic non-small cell lung cancer were treated by a combination of ifosfamide (3 days), sodium 2-mercaptoethane sulfonate (4 days), and etoposide (8 days). Cycles were repeated every 28 days. Ifosfamide was administered orally, with the exception of one of the first two cycles, when it was administered as a short infusion (randomly assigned). The patients received methylene blue in doses of 50 mg po 3 times daily; an initial dose of 50 mg was given the evening before chemotherapy. Urine samples were collected over the entire treatment period, and concentrations of ifosfamide and its major metabolite, 2-chloroethylamine, were measured by gas liquid chromatography. By the same technique, 2- and 3-dechloroethylifosfamide were determined in plasma and urine. Overall alkylating activity in urine was assayed by reaction of the alkylating metabolites with 4-(4'-nitrobenzyl)-pyridine. The chemotherapeutic regimen was well-tolerated by all of the patients studied. There was no evidence of a shift in the metabolic pattern dependent on the route of administration. From the data, we conclude that methylene blue has a neuroprotective effect and that the pharmacokinetics of ifosfamide are not influenced by its comedication.

Administration, Oral↗

PubMed1997

Breast cancer: pretreatment drug resistance parameters (GSH-system, ATase, P-glycoprotein) in tumor tissue and their correlation with clinical and prognostic characteristics.

BACKGROUND: The identification of new factors predicting relapse, outcome and response to systemic therapy in breast cancer is warranted. The measurement of biological markers such as drug resistance parameters (DRPs), which are part of the phenotype of malignant cells and contribute to resistance to anti-cancer drugs may be a possibility, which may ultimately lead to improvement of therapeutic results. PATIENTS AND METHODS: The level of glutathione (GSH), activities of glutathione-S-transferase (GST), glutathione-peroxidase (GPx), 06-alkylguanine-DNA-alkyltransferase (ATase), and P-glycoprotein (PGP) were measured in tumor and adjacent tumor free tissue samples from 89 consecutive, untreated females with breast cancer and correlated with clinical and prognostic factors. Early breast cancer (EBC) was diagnosed in 56 patients, 22 patients had locally advanced (LABC) and 11 patients metastatic breast cancer. RESULTS: All DRPs showed significantly higher expression in tumor than in tumor free tissues. GPx was positively correlated with GST (r = 0.3, P = 0.0048) and with GSH (r = 0.5, P = 0.0001) in tumor as well as in normal tissue. GST activity was significantly higher in EBC than in LABC or metastatic breast cancer (P = 0.02). GSH level was significantly higher in grade 1 than in grade 2 or grade 3 tumors (P = 0.01). When clinical characteristics were related to the level of DRP, 'high' GSH was associated with age > 60 years (P = 0.01) in EBC, and with grade 1-2 tumors (P = 0.05) in LABC. No differences in OS were apparent between groups of 'high' and 'low' DRP-expression. However, the four-year estimated disease-free survival of EBC tended to be higher in patients with 'high' GST (P = 0.10) and of LABC in patients with 'high' GPx levels (P = 0.06). CONCLUSION: We conclude that 'high' levels of DRP in tumor tissue of breast cancer patients are part of the initial phenotype of the malignant cells. Due to its high prevalence (83% in EBC, 100% in primarily metastatic breast cancer), PGP did not add to prognostic information. High levels of GSH, GST and GPx were associated with favorable clinical characteristics and good prognosis, whereas low levels of GSH and GST activity were associated with more aggressive or more advanced disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer.

BACKGROUND: The toxicity profile of prolonged infusions of paclitaxel in combination with cyclophosphamide in metastatic breast cancer has already been defined. The objective of this dose-finding study was to determine the maximum tolerable doses (MTDs) of shorter (three-hour) infusions of paclitaxel in combination with i.v. bolus cyclophosphamide in patients who had previously received a maximum of one chemotherapy for advanced breast carcinoma. The MTD of the same regimen with granulocyte colony-stimulating factor (G-CSF) support was then established. PATIENTS AND METHODS: Eighty women with metastatic breast cancer received a total of 352 fully evaluable courses of therapy. The starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2 given every three weeks. At least three patients were treated at each dose level and if there were dose-limiting toxic effects during the first cycles three additional patients were entered. G-CSF support (5 micrograms/kg s.c.) was added to the second cycle if specific dose-limiting toxicities had occurred during the first cycle. The MTD was defined as the dose level at which more than two of six patients presented dose-limiting toxicities during the first cycle. RESULT: Febrile neutropenia (n = 4) and severe thrombocytopenia (n = 1) defined the MTDs of paclitaxel as 200 mg/ m2 and of cyclophosphamide as 2,000 mg/m2 with or without G-CSF in patients with and, respectively, without prior chemotherapy for advanced disease. Non-hematologic toxicity was moderate. Recommended doses were 200 mg/m2 of paclitaxel and 1,750 mg/m2 of cyclophosphamide with or without G-CSF in patients with and, respectively, without prior chemotherapy. The overall response rate was 25% and 50%, respectively, in patients with and without prior chemotherapy for metastatic disease. Complete remissions (9%) were reported only in patients without prior chemotherapy; antitumour activity in women with anthracycline-resistant disease, with an 8% response rate (95% CI: 1%-26%), was poor. CONCLUSIONS: Paclitaxel at 200 mg/m2 and cyclophosphamide at 1,750 mg/m2 can be safely administered every three weeks to women with advanced breast cancer. The moderate antitumour activity observed with the schedule tested argues against its use as initial therapy for advanced breast cancer.

Adult↗

PubMed1997

Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: an EORTC early clinical studies group investigation.

BACKGROUND: JM216 is a new oral platinum complex with dose-limiting toxicity myelosuppression, now undergoing phase II evaluation. PATIENTS AND METHODS: JM216 was evaluated as first line therapy in non-small-cell lung cancer. Seventeen patients received 120 mg/m2/day for five days repeated every three weeks. RESULTS: Toxicity was manageable, the commonest side-effects being nausea, vomiting, diarrhoea, constipation and asthenia. Myelososuppression was generally grade < 2 and there were no cases of neutropenic sepsis or bleeding. Thirteen patients were fully evaluable for response. No sustained objective responses were reported. One patient was reported as stable disease had a partial response after three courses but was progressing again after four. An additional five patients had stable disease (46.2%). CONCLUSIONS: Although some patients may have had useful palliation, JM216 did not appear to have significant antitumour activity in non-small-cell lung cancer.

Administration, Oral↗