A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours.

The aim of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and the pharmacokinetic profile (Pk) of bendamustine (BM) on a day 1 and 2 every 3 weeks schedule and to recommend a safe phase II dose for further testing. Patients with solid tumours beyond standard therapy were eligible. A 30-min intravenous infusion of BM was administered d1+d2 q 3 weeks. The starting dose was 120 mg m(-2) per day and dose increments of 20 mg m(-2) were used. Plasma and urine samples were analysed using validated high-performance liquid chromatography/fluorescence assays. Fifteen patients were enrolled. They received a median of two cycles (range 1-8). The MTD was reached at the fourth dose level. Thrombocytopaenia (grade 4) was dose limiting in two of three patients at 180 mg m(-2). One patient also experienced febrile neutropaenia. Lymphocytopaenia (grade 4) was present in every patient. Nonhaematologic toxicity including cardiac toxicity was not dose limiting with this schedule. Mean plasma Pk values of BM were tmax 35 min, t(1/2) 49.1 min, Vd 18.3 l m(-2), and clearance 265 ml min(-1) m(-2). The mean total amount of BM and its metabolites recovered in the first micturition was 8.3% (range 2.7-26%). The MTD of BM in the present dose schedule was 180 mg m(-2) on day 1+2. Thrombocytopaenia was dose limiting. The recommended dose for future phase II trials with this schedule is 160 mg m(-2) per day.

Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone--a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO).

PURPOSE: This randomized phase III study compared bendamustine and prednisone (BP) to standard melphalan and prednisone (MP) treatment in previously untreated patients with multiple Myeloma (MM). PATIENTS AND METHODS: To be included, patients had to have histologically and cytologically proven stage II with progressive diseases or stage III MM. They were randomly assigned to receive BP (n=68) or MP (n=63). The primary endpoint was the time to treatment failure (TTF). Secondary endpoints included survival, remission rate, toxicity and quality of life. RESULTS: The overall response rate was 75% in the BP and 70% in the MP group. A significantly higher number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 13%; P=0.007), and the maximum response was achieved more rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles; P<0.02). TTF and remission duration were significantly longer in the BP group. Patients receiving BP had higher QoL scores and reported pain less frequently than patients receiving MP. CONCLUSION: BP is superior to MP with respect to complete remission rate, TTF, cycles needed to achieve maximum remission and quality of life and should be considered the new standard in first-line treatment of MM patients not eligible for transplantation.

Collective effects in grain boundary migration.

In situ high-resolution transmission electron microscopy is used to study grain boundary structure and kinetics in bicrystalline Au films at elevated temperature. We report the first direct evidence for the existence of cooperative atomic motion in grain boundary migration. Certain nanoregions at grain boundaries, typically involving up to several hundred atoms, are found to switch back and forth between neighboring grains. Reversible structural fluctuations at temperatures near 0.5T(m) and above have been discovered in [110] and [001] tilt, as well as in general grain boundaries.

Regression of brain metastases from breast carcinoma after chemotherapy with bendamustine.

PURPOSE: Bendamustinehydrochloride (bendamustine) is an alkylator with anticipated antimetabolic activity. It has shown activity in malignant lymphoma and breast cancer. Up to now there are no reports about the activity of bendamustine in the treatment of brain metastases. We report on a 38-year-old woman with brain metastases from breast cancer. The first diagnosis of an invasive ductal, hormone receptor negative breast cancer was made in October 1997, stage pT1c pN2 (11/11)cM0 - G3. After lumpectomy and resection of axillary lymph nodes, the patient received adjuvant chemo- and radiotherapy. Twenty six months after the first diagnosis, bone metastases occurred and were treated with radiotherapy. One month later, multiple liver metastases developed which were treated with trastuzumab and paclitaxel. Four months later, progress of the liver metastases and malignant infiltration of bone marrow with thrombopenia occurred. METHODS: Chemotherapy with bendamustine at a dose of 150 mg/m(2) on day 1 and 2 was initiated. Two days later, the patient suffered from central facial palsy and subsequent computed tomography (CT) revealed three brain metastases in the frontal, parietal and occipital region. Because of the advanced liver metastases with clinical and laboratory signs of liver insufficiency and the reduced performance status of the patient, chemotherapy with bendamustine was continued and no local treatment of the brain metastases was performed. RESULTS: After two courses of bendamustine, ultrasound showed regression of the liver metastases. Liver enzymes decreased, platelets increased, and the patient's performance status improved. Additionally, two of the three brain metastases were no longer detectable by CT, the third had decreased compared to the time of diagnosis. CONCLUSION: To the best of our knowledge, this is the first report describing major activity of bendamustine in cerebral metastases. Thus, it may be considered as another therapeutic strategy against metastatic brain cancer. However, this finding warrants further investigation in clinical trials.

Weekly administration of bendamustine: a phase I study in patients with advanced progressive solid tumours.

BACKGROUND: The cytotoxic agent bendamustine combines a purine-like benzimidazol and alkylating nitrogen mustard group. The clinically tolerated dose for single bolus bendamustine is 215 mg/m2, for fractionated therapy on four consecutive days 85 mg/m2. The maximum tolerated dose of a day 1 and 8 (q4w) 30 min infusion schedule was recently found to be 160 mg/m2, mouth dryness and fatigue were dose-limiting. Our current phase I trial was designed to define the recommended dose of a new weekly short infusion schedule. PATIENTS AND METHODS: Patients with refractory malignant tumours qualified for the trial after written informed consent was obtained. Bendamustine was given as a 30-min i.v. infusion weekly for up to eight consecutive weeks. RESULTS: Twelve patients (8 male, 4 female, median age 57.5 years, range 42-64) were enrolled in this trial. At the starting dose of 80 mg/m2, two patients had dose-limiting toxicity (fatigue grade 3, mouth dryness grade 3, fever grade 4 Common Toxicity Criteria). No dose-limiting events were observed in six patients treated at 60 mg/m2. An intermediate dose level of 70 mg/m2 was studied in three younger, less heavily pretreated patients, was well tolerated and not associated with dose-limiting events. Haematological toxicity was mild except for grade 3-4 lymphocytopenia, occurring in 11 of 12 patients. Bendamustine was found to induce long-lasting panlymphocytopenia with predominant B-cell cytotoxicity. CONCLUSIONS: The maximum tolerated dose of weekly bendamustine given as a 30-min i.v. infusion is 80 mg/m2, mouth dryness, fatigue and fever are dose-limiting. The recommended dose for phase II trials is 60 mg/m2.

Repeated administration of short infusions of bendamustine: a phase I study in patients with advanced progressive solid tumours.

PURPOSE: The cytotoxic agent bendamustine combines a purine-like benzimidazol and bifunctionally alkylating nitrogen mustard group. The drug has clinical antitumour activity in lymphoma, myeloma and breast cancer. In earlier dose-finding studies, the clinically tolerated dose for single-bolus bendamustine was 215 mg/m2; for fractionated therapy on 4 consecutive days it was 85 mg/m2. Anticholinergic symptoms, myelosuppression and cardiac dysrhythmia were dose-limiting. Our trial was designed to define the maximum tolerated dose of a short infusion schedule and to establish a recommended dose for ongoing and future clinical studies. METHODS: Patients with refractory malignant tumours qualified for the trial after written informed consent had been obtained. Bendamustine was given as a 30-min iv. infusion on days 1 and 8 of a 4 week cycle, with a starting dose of 100 mg/m2 and an increment per group of 20 mg/m2. RESULTS: Nineteen patients (13 male, 6 female; median age 57 years, range 37-74 years) were treated for one to two cycles with up to 180 mg/m2 bendamustine. At 160 mg/m2, fatigue grade 3 (NCI Common Toxicity Criteria) and dryness of the mouth grade 3 occurred in 2 patients, diarrhoea grade 3 in 1 patient; another patient with a history of myocardial infarction and arrhythmia developed a reversible total atrioventricular block after the first administration of 160 mg/m2 bendamustine. Other events, such as nausea/vomiting, loss of appetite, fever or chills, were not dose-limiting. Haematological toxicity was mild, except for sudden and long-lasting grade 3-4 lymphocytopenia, which occurred in all treatment cycles. Opportunistic infections were not observed. CONCLUSIONS: The maximum tolerated dose of a days-1 and -8 schedule of bendamustine, given as a 30-min i.v. infusion, is 160 mg/ m2; mouth dryness and fatigue are dose-limiting. The recommended dose for future trials is 140 mg/m2.

The effects of sample preparation methods on the variability of the electrospray ionization response for model drug compounds.

A post-column infusion system was developed in order to analyze suppression of electrospray ionization (ESI) tandem mass spectrometry response in the presence of endogenous plasma interferences. By enabling direct detection of these interfering components, this experimental system was used to analyze the ability of several common extraction procedures to remove endogenous plasma components that cause changes in the ESI response of model drug substances. Methyl-t-butyl ether (MTBE) liquid-liquid, Oasis and Empore solid-phase, and acetonitrile (ACN) protein precipitation sample preparation methods were tested using the post-column infusion system. In all cases, ACN protein precipitation samples showed the greatest amount of ESI response suppression while liquid-liquid extracts demonstrated the least. In addition, the three test compounds, phenacetin, caffeine, and a representative Merck compound, demonstrated that ESI response suppression is compound dependent. Suppression was greatest with caffeine, the most polar analyte, and the smallest for the Merck compound, the least polar analyte. Copyright 1999 John Wiley & Sons, Ltd.

Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study.

A phase II pilot study of bendamustine as salvage treatment in patients with advanced breast cancer was performed to determine the objective response rates and make further observations on the toxicity of this drug. A group of 37 patients, pretreated with chemotherapy for advanced disease, entered the trial. Treatment consisted of 150 mg/m2 bendamustine on days 1 and 2 of a 4-week treatment course. Patients continued to receive treatment until complete remission and then two further courses, until tumour progression or unacceptable toxicity ensued. A total of 36 patients received at least one treatment course and were assessable for toxicity; 33 patients were evaluable for treatment results. Dose-limiting grade 3 and 4 WHO toxicity occurred in 5 and 3 patients respectively; 27% of patients entered complete or partial tumour remission. The median time to tumour progression was 2 months with a range of 1-14 months. The efficacy of bendamustine was apparently independent of pretreatment with anthracyclines, suggesting a lack of cross-resistance between bendamustine and anthracyclines. It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer. The toxicity was acceptable. Future studies have to confirm the data of this pilot trial and to define the role of bendamustine in the combination chemotherapy of metastatic breast cancer that has been suggested by previous trials.

[Clinical and radiologic results of surgically treated patellar dislocation]. / Klinische und radiologische Ergebnisse der operativ behandelten Patellaluxation.

In this retrospective study 72 patients were followed up clinically and radiologically after surgical treatment for dislocation of the patella. The period of observation varied between 13 and 76 months, with an average of 32 months. Acute traumatic dislocation of the patella was only rarely encountered (n = 6 [8%]). Primary dislocation occurred most frequently during the second and third decades of life. Chondral and osteochondral fractures were fairly frequent (n = 24 [33%]). Additional injuries involved the anterior cruciate ligament, the medial collateral ligament and the menisci. At clinical examination 32 patients (44%) could be assessed as "very good" and "good" (classification of Larsen and Lauridsen). Redislocation occurred in 12 patients (16.7%). The radiological condition of the patella and that of the trochlea femoris were assessed in terms of the classification of Wiberg and Baumgartl and of Hepp, respectively. The condylar-joint angle (Brattström) and the condylar depth index (Ficat and Bizou) were also evaluated.

[The radiation-sensitizing effect of isometronidazole following its intravesical application in bladder carcinoma. A clinical phase-II study]. / Die strahlensensibilisierende Wirkung von iso-Metronidazol nach intravesikaler Applikation beim Harnblasenkarzinom. Eine klinische Phase-II-Studie.

The radiosensitizing efficacy of iso-metronidazole, a 4-nitroimidazole derivative, was evaluated in a prospective clinical phase-II study. The results of combined radiotherapy of 25 patients with bladder cancer were compared with those of a control group of 25 patients treated with radiotherapy only. Tumor regression six months after radiotherapy was used as an endpoint. The surgical procedure was performed as double TUR. Evaluating the local tumor control after additional application of iso-metronidazole a gain factor of 1.2 is obtained.

[The immediate results of the use of isometronidazole in the combination therapy of patients with lung cancer]. / Neposredstvennye rezul'taty primeneniia izometronidazola pri kombinirovannom lechenii bol'nykh rakom legkogo.

The paper is devoted to assessment of isometronidazole tolerance, used as a radiosensitizer for preoperative irradiation of lung cancer patients, and to characterization of morphological postradiation changes in tissues of carcinomas removed at operation. Isometronidazole was shown to cause no severe side-effects in patients, improving considerably radiation injury of the tumor parenchyma.

Quality assurance in radiotherapy--a clinical view-point.

Despite the advanced treatment methods now available, the total result in 5-year survival is 40-50% of all patients with malignancies and 20% of these patients will have the chance of a 10-year survival. In the course of their disease a radiotherapy is indicated in about 2/3 of all cancer patients. Thus, radiotherapy makes quite a considerable contribution to the qualitative improvement of the treatment of patients with malignancies. Eradication of the tumor and protection of normal tissue can be only a compromise between tumor control and the production of complications. For the risk assessment of radiotherapy, the steepness of dose-response curves is of paramount importance. That means, small errors in defining and delivering dose can have catastrophic results in terms of failure to control the patient's disease and, on the other side, in terms of complications, that means in quality of life. Although the costs of therapy, in absolute values, vary from one country to the other, it can be stated in rough approximation that a failed radiotherapy will make rise the costs by a factor of 3. Proceeding on the fact that in 30-40% of patients, who received radiotherapy, the initial treatment failed to control the primary disease, the enormous additional costs involved become obvious, not to speak of the main argument--the regrowth of the patient's tumor. For the improvement of this situation quality assurance (QA) is an essential prerequisite, which should be guaranteed in all successive steps of radiotherapy. In the paper an analysis is given for all individual steps in the chain of radiotherapeutic measures.(ABSTRACT TRUNCATED AT 250 WORDS)

[Calculation of the relative biological efficiency (RBE) of neutron radiation]. / Zur Berechnung der Relativen Biologischen Wirksamkeit (RBW) von Neutronenstrahlung.

The Relative Biological Effectiveness (RBE) of radiation with different LET has to be recognized in the planning of radiation therapy especially if one type of radiation should be replaced by another type or if both should be used within the same irradiation course. In radiation therapy it is suitable to consider the RBE in connection with dose dependent cell survival rates. These rates can be described by means of corresponding mathematical models. A simple way to calculate the RBE on the basis of the modern LQ-model is demonstrated. In that procedure the alpha/beta-ratios which are known at least approximatively for many organs and tissues can be used. The proposed method is demonstrated for the human skin and lung. For these organs we obtained RBE ranges from 3.4 to 1.2 and from 3.8 to 0.8, respectively, considering increasing doses. Thereby, for the lung it can be observed that the dose dependency of the RBE for small doses is especially strong. The obtained results are in good coincidence with experiences in clinical practice.

[A comparison of systemic radiotherapy, chemotherapy or local radiotherapy in the treatment of extensive small-cell bronchial carcinoma. Results of a randomized series]. / Vergleich zwischen systemischer Strahlentherapie, Chemotherapie oder lokaler Strahlentherapie bei der Behandlung des ausgedehnten kleinzelligen Bronchialkarzinoms. Ergebnisse einer randomisierten Serie.

Between 1982 and 1987 we carried out a prospective randomized study to compare the effectiveness of high-dose half-body irradiation (HBI) (A), intensive combined chemotherapy (B), and local or locoregional radiotherapy (C) in the therapy of extended small cell lung carcinoma (SCLC). 99 patients with a histologically proved SCLC were assigned to the three therapeutic groups of series: A = 31 patients, B = 37 patients, C = 31 patients. The median survival period showed a statistically significant advantage (p less than 0.01) for the chemotherapy group (B = 46 weeks) versus the two radiotherapy groups (A = 19 weeks, C = 23 weeks). The survival after half a year, one year, and two years also gave a clear advantage for the chemotherapy group. No difference was found between the radiotherapy groups A and C. The high-dose HBI gave no improvement of the sad therapeutic situation for the extended SCLC.

[Does the initial hemoglobin value modify the primary tumor reaction? A study of 264 irradiated bronchial cancers]. / Beeinflusst der initiale Hämoglobinwert die Primärtumorreaktion? Eine Untersuchung an 264 bestrahlten Bronchialkarzinomen.

In a retrospective investigation the remission rate was determined in roentgen picture for 264 male patients with bronchogenic carcinoma after intensive radiotherapy (target dose 56 Gy). Classification of roentgenologic remission was done in 3 groups (complete, partial, minimal/no remission). For each patient the pretherapeutic haemoglobin value was taken from casebook and clinical relevant limit concentrations for an anaemia were correlated with the classified remissions. The difference of regression frequency between complete and partial remission always can be secured statistically irrespectively of chosen limit, that is the anaemia has a provable influence on roentgenologic tumor reaction. To prove that the tumor value as a third variable is not responsible for that a covariant analysis was done. According to that the corrected mean haemoglobin values were 8.9 mmol/l for complete, 8.1 mmol/l for partial and 7.7 mmol/l for minimal/no remission. These differences of the mean values are significant in Newman-Keuls-test, the relation between initial haemoglobin value and remission type is provable independently of tumor volume. Also for bronchogenic carcinoma with that a dependence could be shown between haemoglobin concentration--and by this the oxygen supply of the tumor--and the reaction of the primary tumor after radiotherapy. From this we deduce the recommendation to treat anaemia before beginning of radiotherapy or to irradiate anaemic patients applying an effective sensitizer.

[Current problems of topometric irradiation planning]. / Aktuelle Probleme der topometrischen Bestrahlungsplanung.

Starting from the chain of single steps in radiotherapy, the requirements of topometrical treatment planning are defined and current directions of development for the improvement of accuracy and clearness of treatment plans are shown. By far not all the possibilities of ultrasound tomography (UST) and NMR-tomography for use in radiotherapy have been clarified up to now. Particularly in case of UST the range of application in radiotherapy can be essentially widened due to technical developments. Computerized tomography (CT) today holds a very important place in radiotherapy. In the centre of current interest are simulators able to produce CT and computerized tomographs with the possibility to use them as simulators. Pinpointing some of such developments, the importance of three-dimensional treatment planning with its diverse possibilities is detailed. They put the physician and the physicist in a position to imagine and to interpret quickly and effectively the enormous variety of data in treatment planning.

[Experiences with intensive radiotherapy of prostatic cancer in conjunction with surgery (transurethral resection, pelvic lymph node excision)]. / Erfahrungen bei der intensiven Strahlentherapie des Prostatakarzinoms im Zusammenhang mit operativen Eingriffen (TUR, PLA).

Since 1981 a curative radiation treatment was performed in 84 patients with prostatic carcinoma. Previously, in 37 cases a transurethral resection of bladder outlet obstruction was done and in 18 patients a pelvic lymph node dissection was performed, whereas 29 patients were without operative therapy. Mild side effects of radiation could observed in all 3 groups in nearly the same portion (59/56/65%). However, in the group with transurethral resection after follow-up of 4,4 years severe late complications were found (cystitis, incontinence, urethral fistula). Therefore, radiation treatment of prostatic carcinoma after transurethral resection was abandoned. The cumulative 5-year-survival rate was 63% and in the TUR group only 41%. 9 out of 10 patients with histological verified lymph node metastases and radiation treatment are alive after mean follow-up time of 3.1 years without evidence of recurrent disease.

A randomized clinical trial comparing systemic radiotherapy versus chemotherapy versus local radiotherapy in small cell lung cancer.

Between 1982 and 1987 a prospectively randomized trial of sequential hemibody irradiation (SHBI) (A), a non-cross-resistant chemotherapy drug combination (B) and local and/or locoregional radiotherapy (C) in small cell lung cancer (SCLC) was conducted. Previously untreated patients with extensive SCLC were randomized into three arms: A = 31 patients, B = 37, C = 31. In the chemotherapy combination, the following were used: etoposide, doxorubicin, methotrexate (VAM) and procarbacine, vincristine, cyclophosphamide, lomustine (POCC) and prophylactic cranial irradiation (30 Gy). The results show that the median survival was significantly (P less than 0.01) better in chemotherapy (44 weeks) compared with 17 and 20 weeks in arms A and C, respectively. One year and 2 year survival rates were better for the chemotherapy arm. No differences were found between groups A and C. In comparing the total hospitalization time expressed as a percentage of overall survival, an advantage for group B was shown. In conclusion, high dose SHBI cannot be recommended as a standard therapy for extensive SCLC.