Evaluation of the prognostic significance of disseminated tumor cells in the bone marrow of primary, non-metastatic breast cancer patients after a 7-year follow-up.

PURPOSE: About 30% of primary, non-metastatic breast cancer patients show a relapse of the disease years after first diagnosis, probably due to early tumor cell spread to the bone marrow (BM). For disseminated tumor cells (DTCs) in the BM, tumor cell dormancy, stem cell-like features and discordant receptor status of DTCs as compared to the primary tumor have been described, explaining the failure of conventional therapies. Here, we demonstrate no prognostic impact of DTCs and explain these findings by early bisphosphonate intake. METHODS: Bone marrow aspirates of 394 patients with first diagnosis of breast cancer diagnosed between July 1997 and February 2003 were evaluated for DTCs, applying immunocytochemistry. In addition to the given therapy including chemotherapy, radiotherapy and anti-hormonal therapy, oral clodronate therapy was recommended for at least 2 years for all DTC-positive patients. BM results were correlated with clinical prognostic factors and overall survival (OS). RESULTS: Disseminated tumor cells were detected in 163/394 (41%) patients and significantly correlated with a histopathological lobular subtype (p = 0.032) and inversely with HER2 positivity (p = 0.01). After a median follow-up of 7 years, no significant differences with regard to OS could be demonstrated for DTC-positive patients as compared to patients with no DTCs in the BM at first diagnosis (p = 0.156). CONCLUSIONS: In this study, we demonstrate no prognostic impact of DTCs, contradictory to previous findings. We speculate that the lack of impact of DTC-positivity on OS might be due to early clodronate intake, but further studies will have to prove whether the observed effect can be confirmed.

Final results from the prospective phase III WSG-ARA trial: impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer.

BACKGROUND: WSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC). PATIENTS AND METHODS: One thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA-; n = 619). DA (500 µg q3w) was started at hemoglobin (Hb) levels <13.0 g/dl (<12 g/dl after DA label amendment) and stopped at Hb levels ≥14.0 g/dl (12 g/dl after label amendment). Primary efficacy end point was event-free survival (EFS); secondary end points were toxicity, quality of life (QoL) and overall survival (OS). RESULTS: Venous thrombosis (DA+: 3.0%, DA-: 1.0%; P = 0.013) was significantly higher for DA+, but not pulmonary embolism (0.3% in both arms). Median Hb levels were stable in DA+ (12.6 g/dl) and decreased in DA- (11.7 g/dl). Hb levels >15 g/dl were reported in 0.8% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3%, DA-: 87.5%; Plog-rank = 0.55) or OS (DA+: 95.5%, DA-: 95.4%; Plog-rank = 0.77). CONCLUSIONS: DA treatment did not impact EFS or OS in routine adjuvant BC treatment.

A randomized phase III adjuvant study in high-risk cervical cancer: simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): a NOGGO-AGO Intergroup Study.

BACKGROUND: Simultaneous adjuvant platinum-based radiochemotherapy in high-risk cervical cancer (CC) is an established treatment strategy. Sequential paclitaxel (Taxol) and platinum followed by radiotherapy may offer further advantages regarding toxicity. PATIENTS AND METHODS: An open-labeled randomized phase III trial was conducted to compare paclitaxel (175 mg/m(2)) plus carboplatin (AUC5) followed by radiation (50.4 Gy) (experimental arm-A) versus simultaneous radiochemotherapy with cisplatin (40 mg/m(2)/week) (arm-B) in patients with stage IB-IIB CC after surgery. Primary objective was progression-free survival (PFS). RESULTS: Overall, 271 patients were randomized and 263 were eligible for evaluation; 132 in arm-A and 131 in arm-B appropriately balanced. The estimated 2-year PFS was 81.8% [95% confidence interval (CI) 74.4-89.1] in arm-B versus 87.2% (95% CI 81.2-93.3) in arm-A (P = 0.235) and the corresponding 5-year survival rates were 85.8% in arm-A and 78.9% in arm-B (P = 0.25). Hematological grade 3/4 toxicity was higher in arm-B. Alopecia (87.9% versus 4.1%; P < 0.001) and neurotoxicity (65.9% versus 15.6%; P < 0.001) were significantly higher in arm-A. Early treatment termination was significantly more frequent in arm-B than in arm-A (32.1% versus 12.9%; P = 0.001). CONCLUSIONS: Sequential chemotherapy and radiation in high-risk CC could not show any significant survival benefit; however, a different toxicity profile appeared. This sequential regime may constitute an alternative option when contraindications for immediate postoperative radiation are present.

Epoetin beta (NeoRecormon) therapy in patients with solid tumours receiving platinum and non-platinum chemotherapy: a meta-analysis.

BACKGROUND: Anaemia is a common complication of chemotherapy (CT), including both non-platinum (Pt)-based as well as Pt-based CT. PATIENTS AND METHODS: Patients from three controlled trials with solid tumours receiving either Pt- or non-Pt-based CT, who had been randomised to epoetin beta treatment or standard care, were included in this meta-analysis (n=255, n=199, respectively), to see if epoetin beta was equally effective in both CT types. The primary endpoint was haemoglobin (Hb) change. Secondary end-points included transfusion requirement, adverse events (AEs), survival, time to tumour progression and thromboembolic events (TEEs). RESULTS: All patients responded rapidly to epoetin beta treatment, showing a median Hb increase of > or = 1 g/dl from baseline at week 4. A median Hb of 12.2, 12.5 and 11.8 g/dl was achieved in all patients, those receiving Pt-based CT and those receiving non-Pt-based CT, respectively, after 16 weeks of treatment. Transfusion risk reductions associated with epoetin beta treatment of 53% (p<0.0001), 61% (p<0.0001) and 26% (non significant) were observed for all patients, Pt- and non-Pt-based CT patients, respectively. Overall, for all three populations, there were no risks identified for tumour progression or overall survival. There was a statistically non-significant incidence of TEEs (5.9% versus 4.5%) and no marked differences were observed between groups for frequency or type of AEs reported. CONCLUSION: The type of CT has no impact on the ability of epoetin beta to rapidly increase Hb in patients with solid tumours and CT-induced anaemia.

Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies.

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed. At 56 g/m2, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m2 treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m2. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.

WITHDRAWN: The safety of synthetic paclitaxel by intralesional delivery with OncoGeltrade mark into skin breast cancer metastases: method and results of a clinical pilot trial.

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[Pros and cons of early cancer detection in breast carcinoma]. / Das Mammographie-screening ist zur Früherkennung geeignet ... aber die Qualität der Vorsorge muss stimmen.

Mammography is an appropriate method for the detection of early forms of cancer of the breast, and for reducing mortality. Whether this actually succeeds depends upon the quality of the early detection strategies employed. Currently the data on reduction of mortality by mammographic screening remain ambivalent.

A summary of two clinical studies on tumor cell dissemination in primary and metastatic breast cancer: methods, prognostic significance and implication for alternative treatment protocols (Review).

Although only less than 10% of women with primary breast cancer have clinicopathologic signs of overt metastases, metastatic relapse occurs in about half of the cases with apparently localized tumors within five years after surgery. In 23% of the patients, bone marrow metastases are detectable at first relapse and this rate even increases in patients with metastatic breast cancer. However, hematogeneous or lymphatic spread of occult tumor cells can arise before diagnosis at an early stage of primary tumor growth and is regularly underestimated by currently available clinical and pathologic staging procedures. We studied cytokeratin-positive (CK+) cells in the bone marrow (BM) and tumor markers in the blood of 128 patients with primary breast cancer in order to obtain an early diagnosis of residual disease. In a second study, we monitored cytokeratin (CK)/17-1A positive cells in the BM and peripheral blood stem cells (PBSC) to evaluate whether dose intensive or high-dose (HD)-chemotherapy can eliminate micrometastases in high-risk breast cancer patients. The overall CK+ rate was 34% (44/128 patients), 29% (15/51) for patients with T1 tumors, 33% (28/84) for N0 patients and 31% (26/82) for patients with G1-2 breast carcinoma. Interestingly, 67% of CK+ patients were only positive in one of the two BM aspirates studied. At least one tumor marker including carcinoembryonic antigen, carbohydrate antigen 15-3 and tissue polypeptide antigen, was increased in 58/128 (45%) patients [21/58 (36%) were CK+ in the BM]. Surprisingly, levels for the extracellular domain of Her-2/neu in serum samples were within the normal range in every patient studied. After a 2-year follow-up, 7/128 patients relapsed (3/7 CK+/TM-; 2/7 CK-/TM+; 2/7 CK-/TM-). We concluded that studying two BM aspirates for CK+ cells by immunocytochemistry in combination with tumor marker determination is useful for identifying patients with a higher risk for relapse. A tumor cell enrichment technique, applied in 70 patients prior to immunocytochemistry using dynabeads directly coupled to an antibody (BerEp4) targeting the 17-1A antigen, did not enhance the detection rate of disseminated tumor cells in this patient group. We monitored CK+/17-1A+ cells in the BM and PBSC and studied Her-2/neu serum levels of patients with locally advanced (n=13, group 1) and metastatic breast cancer (n=30, group 2). CK+ cells were found in the BM of 3/13 (23%) group 1 patients before but not after chemotherapy resulting in an overall survival (OS) of 92% after a median follow-up of 33 months. Contamination of PBSC in 2/9 (22%) patients was not associated with decreased survival. In group 2 patients, the CK+ rate was 60% (18/30 patients) before and 40% (4/10 patients) after therapy with an OS rate of 43% after 29 months. PBSC samples were positive in 7/24 (29%) patients. CK+ BM and PBSC led to a rapid progress and short OS whereas tumor cell free BM and PBSC resulted in a mean OS of 30 months. The antigen 17-1A was detected on most CK+ cells in both patient groups before therapy, on all CK+ PBSC and on CK+ cells in group 2 patients after therapy. Increased Her-2/neu levels were found in group 2 patients before chemotherapy. In conclusion, micrometastatic cells are present in blood and PBSC grafts of high-risk breast cancer patients and can survive even HD-chemotherapy. Immunotherapeutic target antigens on the cell surface of these cells support the idea that a combined chemoimmunotherapy might be successful in eliminating minimal residual disease.

High-dose chemotherapy with peripheral blood stem cell transplantation for patients with advanced ovarian cancer.

PURPOSE: We report the results of high-dose chemotherapy (HDC) with peripheral blood stem cell transplantation in twenty-one patients with primarily advanced or relapsed ovarian cancer. METHODS: Twenty-five women underwent stem cell collection, and 21 were finally treated with different regimens of HDC containing cyclophosphamide, etoposide, carboplatin, and treosulfan. The patients received cyclophosphamide +/- cisplatin and cisplatin + paclitaxel, respectively, followed by G-CSF (n = 24) or GM-CSF (n = 1) for stem cell mobilization. RESULTS: A mean of 7.2 +/- 6.1 x 10(6) CD34+ cells per kg bw were collected. Thirteen patients received double transplants and one patient received a triple transplant. The median age was 47 years (range 24-61 years) and the mean number of prior regimens was three (range 1-8). Engraftment occurred on time in all patients and there was one treatment-related death resulting in an overall mortality rate of 4.8% among the 21 patients treated with HDC. The response rate was 72% (48% CR, 24% PR) and the mean time to progression and overall survival after HDC were 7 and 32 months, respectively. CONCLUSION: HDC could be performed safely in patients with advanced ovarian cancer. However, even with a high response rate, the duration of response is short, warranting new treatment approaches to further improve the outcome of this population of patients with unfavorable prognosis.

Plasmatic haemostasis in gonadotrophin-releasing hormone analogue therapy: effects of leuprorelin acetate depot on coagulatory and fibrinolytic activities.

The plasmatic parameters of coagulatory and fibrinolytic activity were studied in 15 patients with biopsy-proven endometriosis treated with leuprorelin acetate for 6 months. Bleeding time remained constant, indicating the absence of increased bleeding tendencies. The activity of the main inhibitor of the fibrinolytic response, plasminogen activator inhibitor, was reduced by 25%, suggesting an improvement in fibrinolytic reactivity. Plasma levels of fibrin degradation fragments were reduced by 35%, suggesting a marked reduction in the rate of fibrin generation and degradation. A simultaneous reduction in thrombin-antithrombin III complexes and prothrombin fragment 1 + 2 (-10%) indicated that this effect was induced by reduced procoagulant activity, ie, thrombin generation. These data indicate that in gonadotrophin-releasing hormone (Gn-RH) analogue therapy the basal rate of coagulatory processes is reduced. The frequency and extent of fibrin-generating and degrading processes are reduced, suggesting a beneficial effect of Gn-RH analogues on the risk of thromboembolic disease.

Investigation of bioavailability and pharmacokinetics of treosulfan capsules in patients with relapsed ovarian cancer.

PURPOSE: Treosulfan (L-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. METHODS: A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration. RESULTS: The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 +/- 0.18 (mean +/- SD) using the values AUC oral = 82.1 +/- 39.4 microg/ml h and AUC i.v. = 85.4 +/- 30.3 microg/ml h. The peak plasma concentration cmax (29 +/- 14 microg/ml vs 65 +/- 23 microg/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 +/- 0.34 h. The terminal half-life of treosulfan was about 1.8 h. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 h (range 6-26%). CONCLUSIONS: The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.

Clinical pharmacokinetics of intravenous treosulfan in patients with advanced solid tumors.

Treosulfan (L-threitol- 1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. For a clinical and pharmacology study, patients with advanced, refractory, or resistant solid tumors were treated with a single-dose intravenous 30-min infusion of 8 or 10 g/m2 treosulfan. A sensitive method for the determination of treosulfan in plasma and urine by reverse-phase high-performance liquid chromatography was developed. A total of 14 plasma and urine treosulfan pharmacokinetics determinations were analyzed in the 8-g/m2 group and 7 were analyzed in the 10-g/m2 group, the maximum tolerated dose for this group of pretreated patients. The terminal half-life of treosulfan was in the range of 1.8 h. AUC and Cmax values were significantly (P < 0.01) higher in the 10-g/m2 group (AUC 708+/-168 versus 977+/-182 microg ml(-1) h, Cmax 465+/-98 versus 597+/-94 microg/ml). The mean urinary excretion of the parent compound was about 25% of the total dose delivered over 48 h (range 5-49%), and about 20% was excreted during the first 6 h after administration. Currently, a clinical phase I pharmacokinetics and dose-escalation trial with autologous blood stem-cell support has been started at 20 g/m2 treosulfan using a 2-h infusion protocol.

Paclitaxel and UFT plus oral calcium folinate in pretreated metastatic breast cancer.

This phase I study was designed to determine the maximum tolerated dose (MTD) and dose-limiting side effects of combination treatment with paclitaxel (Taxol) and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) for advanced metastatic breast cancer. After premedication, patients received paclitaxel as a 3-hour IV infusion (175 mg/m2) on day 1; UFT was administered orally at 300 mg/day (dose level 1), 400 mg/day (dose level 2), 500 mg/day (dose level 3), or 600 mg/day (dose level 4) in combination with 90 mg/day of calcium folinate in three divided doses for 14 days. Twenty patients with pretreated metastatic breast cancer have entered the trial so far. The main toxicity was neutropenia, occurring in 68% of patients. World Health Organization grades 1 and 2 peripheral neuropathy, arthralgia, and myalgia were common but not dose-limiting. All patients had grade 3 alopecia due to paclitaxel. One of six patients treated at dose level 4 experienced a dose-limiting toxicity with neutropenic fever. But within four dose levels MTD was not reached, and the study will continue to accrue patients to dose level 5. Objective responses were observed at all dose levels. In conclusion, the combination of paclitaxel and UFT plus oral calcium folinate seems to be a convenient and effective regimen for patients with pretreated metastatic breast cancer. Phase I is ongoing in order to determine MTD and the recommended dose for phase II testing.

Adjuvant CMF-chemotherapy and haemostasis. Effect of "classical" and "modified" adjuvant CMF-chemotherapy on blood coagulation fibrinolysis in patients with breast cancer.

Effects of "classical" and "modified" adjuvant CMF-chemotherapy on haemostasis were studied in 22 patients with breast cancer receiving cyclophosphamide (100 mg/m2 p.o.; days 1-14 or 600 mg/m2 i.v.; days 1,8), methotrexate (40 mg/m2 i.v.; days 1,8) and 5-fluorouracil (600 mg/m2 i.v.; days 1,8). Blood collection was done prior to chemotherapy on day 1 and 8. A significant decrease of protein C antigen and activity associated with cumulative effects was observed from day 1 to 8. This effect was similar with "classical" and "modified" CMF-chemotherapy but the reduction of protein C was more pronounced with the oral application of cyclophosphamide. In absence of any significant cumulative decrease of other vitamin K-dependent blood coagulation proteins (factor VII, protein S), the simultaneous decrease of protein C activity and antigen indicates a specific influence of CMF-chemotherapy on vitamin K-dependent protein C-synthesis in the liver.

The role of age in the course of breast cancer.

UNLABELLED: BACKGROUND AND QUESTION: A retrospective study was performed. To check the hypothesis whether there is an inverse connection between age and prognosis. PATIENTS AND METHODS: We investigated a total group of 1000 cases with breast cancer primarily and consecutively treated between 1968 and 1986. After grouping the patients by tumor stage and median age various life table analyses were performed to calculate and compare the overall survival. Entry date was the date at diagnosis of a first breast cancer or date at first diagnosis of distant metastasis. RESULTS: Young patients with a tumor size T1 and T2 had a significantly better prognosis than older patients with the same tumor stage. Influence of age became significantly weaker in patients with a T3 and T4 tumor. At least in the patients with a primarily M1 stage hardy any more dependence of age could be demonstrated. Similar results were obtained for the 198 patients which presented a distant recurrence. CONCLUSION: Better general life expectancy of young patients is the cause of substantially better overall survival in curable stages. Advanced breast cancer is a strongly life-threatening factor. The fatal influence of large tumor mass is independent of age.

Perioperative development of a thrombogenic risk profile in patients with carcinomas of the breast: a cause of increased thrombosis.

Within the context of a prospective study we investigated the influence of malignant and benign breast disease on the coagulation systems both prior to and after surgery. In addition we also investigated to what extent individual risk factors aid the formation of a thrombophiliac risk profile. Altogether 50 patients with carcinomas of the breast and 12 patients with benign breast disease were included in the study. The coagulation investigations took place prior to surgery and on the 1st, 3rd, 7th and 10th day following the operation. The results have already revealed that prior to surgery a clear activation of the haemostasis takes place among patients with a carcinoma of the breast. When compared to patients with benign breast conditions there was a far greater plasma level of factor VIII vWF, fibrinogen, thrombin-antithrombin III complex, D-dimer fibrin degradation products, tissue-type plasminogen activator and the activity and the antigen of plasminogen activator inhibitor 1. Also during the postoperative period the malignant tumour was a stimulus for additional increased activity of blood coagulation and fibrinolysis. Individual risk factors such as age, menopausal status, obesity and smoking lead to a thrombogenic risk profile which could provide a possible explanation for the observed increased incidence of thrombosis in breast cancer patients. For the clinical work there is a need for intensive pre- and postoperative monitoring in the cases of patients with malignant tumours including angiological examinations, intensive physiotherapy and a risk-adapted prophylactic anticoagulation.

Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer.

PURPOSE: To define the maximum-tolerated dose (MTD) and to evaluate the dose-limiting toxicities (DLT) of the combination of capecitabine and vinorelbine in patients with metastatic breast cancer who relapse after adjuvant and/or first-line treatment. In addition, we aimed to obtain data on efficacy and safety at the recommended dose. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer after failure of prior chemotherapy (including anthracyclines and/or taxanes) were eligible. Capecitabine was administered with a fixed dose of 1000 mg/m(2) orally twice daily for 2 weeks followed by 1 week rest. One treatment cycle consisted of 6 weeks of treatment containing two treatment periods of capecitabine. Vinorelbine was given intravenously at escalated doses of 25 mg/m(2) (dose level 1) and 30 mg/m(2) (dose level 2) on days 1 and 8, and 22 and 29. RESULTS: Thirty-three patients received a total of 91 cycles of capecitabine and vinorelbine. The median number of administered cycles per patient was three (range one to six). Thirty-one patients were evaluable for toxicity. At dose level 2 four out of seven patients experienced DLTs (nausea/vomiting, febrile neutropenia, grade 4 neutropenia, infection and diarrhea); thus, the MTD was defined. In order to confirm the safety and efficacy, dose level 1 was extended to 24 patients. Two patients [8.3%; 95% confidence interval (CI) 1% to 27%] showed DLTs (hospitalization due to febrile neutropenia and prolonged neutropenia). The main toxicity was neutropenia, which was observed at National Cancer Institute Common Toxicity Criteria grade 3 and 4 in 39% of patients. The overall response rate for capecitabine and vinorelbine was 55% (95% CI 36% to 72.7%), including three patients with a complete remission. The median time to disease progression was 8 months (95% CI 4.3-11.7) with an overall survival of 19.2 months (95% CI 11.3-27.1) based on intention-to-treat analysis. CONCLUSIONS: The combination of capecitabine and vinorelbine can be administered with manageable toxicity and showed significant efficacy for patients with metastatic breast cancer even after failure of a anthracycline- and/or taxane-based therapy.

Hemostatic effects of two oral contraceptives containing low doses of ethinyl estradiol and either gestodene or norgestimate: an open, randomized, parallel-group study.

OBJECTIVE: To determine effects on blood clotting of two modern low-dose monophasic oral contraceptives. SUBJECTS AND METHODS: We measured in vivo markers of intravascular coagulatory and fibrinolytic activity in 40 volunteers randomly assigned to one of two low-dose oral contraceptives (OCs) for 6 months; one contained 35 micrograms of ethinyl estradiol (EE) plus 250 micrograms of norgestimate and the other, 30 micrograms of EE plus 75 micrograms of gestodene. RESULTS: Both formulations increased coagulatory as well as fibrinolytic activity over baseline: circulating reactive products of thrombin increased by 40%, and plasmin activity by 60%, after 3 months of treatment. Six months of OC use increased hemostatic activity substantially over that with 3 months of use. Differences between both OC formulations were marginal and clinically insignificant. CONCLUSION: The data suggest an EE-dose-dependent, balanced activation of in vivo coagulation and fibrinolysis in users of currently available, combined OCs. However, there is considerable consumption of coagulation inhibiting factors, suggesting that women with congenital deficiencies of antithrombin III and protein C should not use combined OCs.

[Effectiveness and tolerance of Navoban (5HT3-receptor antagonist tropisetron) in prevention of cytostatic drug-induced nausea and vomiting in patients with breast carcinomas and gynecological malignancies]. / Wirksamkeit und Verträglichkeit von Navoban (5HT3-Rezeptor-Antagonist Tropisetron) zur Prävention der zytostatikainduzierten Nausea und Emesis bei Patientinnen mit Mammakarzinomen und gynäkologischen Malignomen.

Efficacy and safety of the antiemetic agent Navoban (5HT3-receptor-antagonist Tropisetron) on cytostatic-induced emesis of breast cancers and gynecological cancers was tested in 28 female patients receiving a total of 127 chemotherapy courses containing high (cisplatin), moderate high (cyclophosphamid) or moderate (for example 5 FU) emetogenic cytostatic drugs. We studied antiemetic response rates of Navoban (5 mg/d) during the first 24 hours after administration of the chemotherapy as well as response rates of the "delayed nausea and emesis" (days 2-9 after chemotherapy). A complete response was observed in 103 chemotherapy courses (= 81.1%) during the first 24 hours after chemotherapy and in 93 courses (= 73.2%) for the "delayed emesis". Treatment failures (more than 5 vomiting episodes) during the first 24 hours were present in four courses and for the "delayed emesis" in 11 courses. The side effects of Navoban such as constipation, headache or tiredness were minimum. Therefore no patient refused to receive the necessary chemotherapy. Navoban is, with its single dose application, an effective therapeutic drug for the prevention of nausea and emesis in patients receiving a chemotherapy.