Clofibrate kinetics after single and multiple doses.

The kinetics of chlorphenoxyisobutyric acid (CPIB) were studied in 5 healthy subjects after single 500-mg, 1,000-mg, and 2,000-mg doses of clofibrate, and in steady-state after 8 days' treatment with 1,000 mg twice daily. Maximum plasma concentrations of CPIB were observed 4 to 6 hr after dosing. A mean plasma half-life of 16.7 hr was recorded which was independent of dose and duration of treatment. Total plasma clearance (-Cl) calculated from area under the curve with the use of the total plasma concentration was 5.6 ml/min for the 500-and the 1,000-mg doses but increased to 6.8 ml/min for the 2,000-mg dose and was even higher (8.1 ml/min) in steady-state. This change in -Cl is a consequence of progressive reduction in the plasma protein binding of clofibrate at plasma concentrations above 50 microgram/ml, since -Cl rises in association with reduced protein binding at the high plasma concentrations measured after the 2,000-mg single dose and in steady-state. -Cl and apparent volume of distribution were identical for all doses tested when calculations were based on the nonprotein-bound CPIB concentrations only. Due to the inconsistant protein binding of CPIB, total steady-state concentrations could not be predicted from the single dose kinetic data.

Antimicrobial prophylaxis in immunocompromised patients.

The results of a randomised, prospective trial to investigate the efficacy of prophylactic treatment with ofloxacin during granulocytopenia after cytostatic treatment are presented. 42 patients with metastasised testicular germ-cell tumours entered the study. Cytostatic treatment consisted of at least 4 courses, 2 of which were succeeded by prophylactic treatment with ofloxacin. Three patients undergoing prophylactic treatment developed fever. Fever occurred in 16 patients during control phases (no ofloxacin prophylaxis) of cytostatic treatment. Seven of the 19 infections could be documented microbiologically. No side effects that related to ofloxacin were noted. In conclusion, ofloxacin was highly effective in the prevention of infection and, therefore, should be given prophylactically to patients with granulocytopenia.

Dexverapamil to overcome epirubicin resistance in advanced breast cancer.

Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein-associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer.

Risk/benefit of treating retroperitoneal teratoid bulky tumors.

Inductive polychemotherapy of germinal cell tumors in advanced stages (T0-4N3M0,1) is effective, yet accompanied by serious side effects. Partial remission necessitates resection of the residual tumor. The complications of the salvage operation are tolerable in proportion to its curativity. In a retrospective analysis, we evaluated the occurrence of toxic side effects and the frequency of intra- and postoperative complications in 128 patients with retroperitoneal teratoid bulky tumor. With a follow-up of three to one hundred ten months (means = 43 months), 91 patients (71%) are alive without evidence of disease; 28 patients (22%) died of apparent tumor progression.

Alternatives to CYVADIC combination therapy of soft tissue sarcomas.

The CYVADIC combination has been the preferred treatment for soft tissue sarcomas for the last 10 years. Other combination therapies are necessary, because the remission rate achieved with CYVADIC is only 30%. Alternative therapies for these tumors are combinations including cis-platinum, ifosfamide, epipodophyllin, and high-dose methotrexate. Our therapeutic results with combinations of cis-platinum and ifosfamide are comparable to those achieved with CYVADIC. However, the side-effects, such as nausea, vomiting and fatigue, of cis-platinum used in the palliative treatment of these tumors are intolerable for many patients. A combination of adriamycin and ifosfamide, which leads to a higher remission rate of 44% and has lower toxicity than CYVADIC, is giving encouraging results.

Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.

Modified neoadjuvant therapy regime with low dose irradiation in advanced head and neck cancer patients: preliminary results of a pilot study to minimize side effects.

We analysed the files of 52 patients with advanced head and neck tumors who were treated in a pilot phase. The therapy consisted of two courses of induction chemotherapy with ifosfamide and cisplatin followed by hyperfractionated-accelerated radiotherapy with a total dose of only 30 Gy. Surgery was performed within the following 7 days with tumor resection and neck dissection. Histologically we found in 50% of the specimens total necrosis of the tumor. The median survival time is calculated to be 22 months. The median follow-up time thus far is 36 months. Hence, therapy results are comparable to other therapy schedules. But side effects, especially late side effects had become minor. Therefore, our therapy regime results in augmentation of the quality of life of these patients.

[Initial results of in vivo 31P-NMR spectroscopy of the spleen in patients with splenomegaly]. / Erste Ergebnisse der in-vivo-31P-NMR-Spektroskopie der Milz bei Patienten mit Splenomegalie.

In-vivo 31P-NMR spectroscopy of the spleen was carried out in 15 patients with splenomegaly from various causes (Hodgkin's disease, non-Hodgkin lymphoma, polycythaemia vera, chronic lymphatic leukaemia, chronic myeloid leukaemia). Volume selection was with the ISIS technique, voxel size was between 3 x 5 x 5 and 8 x 6 x 7 cm3. There was a markedly elevated (PM+Pi)/beta-NTP quotient (mean 3.41 with a standard deviation of 0.37) (p < 0.001) and raised PDE/beta/NTP quotient as compared with 8 normals, who showed an (PME+Pi)/beta-NTP quotient of 2.32 and a PDE/beta/NTP quotient of 1.11. These raised quotients were interpreted as indicating increased membrane phospholipid metabolism due to increased cell turnover. The data suggest there may be some clinical value in performing 31P-NMR spectroscopy for defining splenic involvement in myeloproliferative diseases but further confirmatory studies will be necessary.

[The results of the chemoembolization of advanced hepatocellular carcinomas. The effect on the survival times, morphological findings and tumor markers]. / Ergebnisse der Chemoembolisation fortgeschrittener Leberzellkarzinome. Einfluss auf Uberlebenszeiten, morphologische Befunde und Tumormarker.

Chemoembolization is a well-recognized therapeutic procedure in the treatment of stage I and stage II hepatocellular carcinoma (HCC). Until now it is rarely used in the treatment of stage III HCC. In a prospective study we analysed the efficacy and the side effects of chemoembolization in 16 patients with stage III HCC. Chemoembolization was performed with an emulsion of lipiodol, 4-epirubicin and cisplatinum. All patients tolerated the treatment without remarkable complications. With 9 months the median survival rate was considerable higher than the survival rate of untreated patients and of patients treated with systemic chemotherapy or with local perfusion.

[Multiple circular liver foci in latent porphyria cutanea tarda]. / Multiple Leberrundherde bei latenter Porphyria cutanea tarda.

A 41-year-old patient with latent porphyria cutanea tarda is described; 8 years after mastectomy for carcinoma, sonography and CT showed multiple hepatic foci, which were at first interpreted as liver metastases. A liver biopsy was carried out during laparoscopy and u/v fluorescence and subsequent laboratory tests confirmed the diagnosis of porphyria cutanea tarda. Treatment with resochin produced almost complete resolution of the liver abnormalities within 9 months. Magnetic resonance tomography using proton-weighted SE sequences showed a few foci of high signal intensity.

[Manganese-DPDP in the MR tomography of malignant liver tumors. The initial results with a new hepatobiliary contrast agent]. / Mangan-DPDP in der MR-Tomographie maligner Lebertumoren. Erste Ergebnisse mit einem neuen hepatobiliären Kontrastmittel.

The new hepatobiliary contrast agent Mangan-DPDP, unlike extracellular Gd-DTPA, leads to a constant increase in signal intensity of normal liver tissue in MR imaging of the liver which lasts at least for 30 minutes. In 19 patients with malignant liver tumors there was no difference in the contrast between tumor and liver when using a dose of 5 or 10 mumol/kg. Contrast enhanced T1-w SE- and T1-w GE sequences show a significant increase in tumor/liver contrast compared with T1-weighted unenhanced sequences. This increase was also significant when compared with T2-w SE sequences. In 16% additional focal lesions were detected on the enhanced scan.

[MR venography in deep venous thromboses of the leg and pelvis. A comparison of 2D single layer images and 3D MIP reconstructions with phlebography]. / MR-Venographie bei tiefen Bein- und Beckenvenenthrombosen. Vergleich von 2D-Einzelschichtbildern und 3D-MIP-Rekonstruktionen mit der Phlebographie.

A total of 22 MR venograms were performed in 7 volunteers and 15 patients suspected of deep vein thrombosis of the lower limb and pelvis. MR findings were compared to conventional venography in all patients. MR venography is a reliable method for the exclusion of thrombosis proximal to the popliteal vein. In the calf veins, diagnosis of thrombosis is not yet reliable. For MR venography 2D-time-of-flight-inflow-technique and secondary 3D-MIP reconstructions were used and compared to each other. With both methods there were no false negative results in comparison to conventional venography. 2D single slice MR venography showed two false positive results in iliac and one in popliteal vein. MIP 3D reconstructions led to seven false positive results (three iliac, two femoral, two popliteal). The exclusive interpretation of MIP-3D reconstruction is not reliable for decision-making in deep venous thrombosis.

Clinical results of immunoscintigraphy in a variety of malignant tumors with special reference to immunohistochemistry.

Radioimmunoscintigraphy was performed in 52 patients with a variety of malignant tumors (colorectal, melanoma, lung, testicular, ovarian, bladder, carcinoid). Respective antibodies or their F(ab')2 fragments against CEA (n = 23), melanoma antigen 225.28 S (n = 18), TPA (n = 4), beta HCG (n = 5) and HMFG2 (n = 2) were selected by immunohistochemistry of the primary tumor. Most patients were suspected of recurrence or of hitherto unknown distant or local metastases. Overall accuracy was 61% (32/52). False negatives amounted to 33% (17/52). Useful additional clinical information-not available by CT, ultrasonics or serum levels of tumor markers-was obtained in 17 out of 52 patients (= 33%). From these results it seems obvious that antibodies used for radioimmunoscintigraphy should be selected on the basis of immunohistochemistry.

[Risk and benefit of the treatment of bulky retroperitoneal teratoid tumors]. / Risiko und Nutzen der Behandlung retroperitonealer teratoider "Bulky"- Tumoren.

Inductive polychemotherapy of germinal cell tumors in advanced stages (T0-4N3,4M0,1) is effective, but is accompanied by serious side effects. If partial remission occurs, it is necessary to resect the residual tumor. The complications involved in this salvage operation are tolerable in relation to the prognosis. In a retrospective analysis, we evaluated the occurrence of toxic side effects and the frequency of intra- and postoperative complications in 128 patients with retroperitoneal teratoid bulky tumor. After a follow-up period of 3-110 months (mean = 43 months), 91 patients (71%) are still alive with no evidence of disease; 28 patients (22%) have died of apparent tumor progression.

[Chemotherapy of malignant testicular tumors]. / Chemotherapie maligner Hodentumoren.

The role chemotherapy plays in the improvement of prognosis of malignant testicular germ cell tumors is discussed in the light of the development of chemotherapeutic conceptions and stage related strategies. The course of disease in 117 own patients being subjected to cytostatic treatment in 1978-1982 is analysed in detail. In 70% of the cases a complete remission was achieved. Partial remissions generally were of short duration. All toxic side effects are described, the vital threat of panmyelopathy with resulting septicaemia being emphasized. The therapeutic countermeasures are mentioned. Protocols of two prospective clinical trials attempting to answer some of the still open questions regarding chemotherapy are presented.

[Gemcitabine/cisplatin vs. MVAC. 5 year survival outcome of the phase III study of chemotherapy of advanced urothelial carcinoma in Germany]. / Gemcitabin/Cisplatin vs. MVAC. 5-Jahres-Ergebnisse der Phase-III-Studie zur Chemotherapie des fortgeschrittenen Urothelkarzinoms in Deutschland.

Of 405 patients with stage IV transitional cell carcinoma from an international multicenter phase III trial, 70 were randomized in Germany to receive either gemcitabine/cisplatin or standard MVAC systemic chemotherapy for locally advanced or metastatic urothelial cancer. Overall survival as the primary endpoint of the study was similar in both arms (median survival GC 15.4 months vs MVAC 16.1 months), as were tumor-specific survival and time to progressive disease. In the intent-to-treat analysis, the 5-year overall survival rate was 10% for patients randomized to GC and 18% randomized to MVAC. Tumor overall response rates (GC 54%, MVAC 53%) were similar. The toxic death rate was 0% in the GC arm and 3% (one patient) in the MVAC arm. Significantly more GC than MVAC patients experienced grade 3/4 anemia (GC 52%, MVAC 20%) with significantly more red blood cell transfusions in the GC arm.Significantly more GC than MVAC patients had grade 3/4 thrombocytopenia (GC 54%, MVAC 17%) without grade 3/4 hemorrhage or hematuria in either arm. More MVAC patients experienced grade 3/4 neutropenia (GC 56%, MVAC 61%, p=1.000), neutropenic or leukopenic fever (GC 0%, MVAC 10%, p=0.237), mucositis (GC 0%, MVAC 7%, p=0.495), and alopecia (GC 6%, MVAC 36%, p=0.004). GC represents a reasonable alternative for the palliative treatment of patients with locally advanced and metastatic transitional cell carcinoma. Sustained long-term survival was only found for patients with locally advanced cancer, lymphatic metastases, or solitary distant metastasis but not for visceral metastatic disease.