Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy.

PURPOSE: Bendamustine hydrochloride, an anti-neoplastic agent with unique mechanism of action, is known to cause impressive remissions in relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukaemia (CLL). Optimal bendamustine dosing for CLL patients had not been finally established and a phase I/II study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of bendamustine. METHODS: The open-label, single-centre phase I/II study was conducted from March 2001 to September 2002 in Sofia, Bulgaria. The 15 study patients were extendedly pre-treated, but fludarabine-naive (3 female, 12 male, 47-72 years of age, 61 years on average). Bendamustine was given at a starting dose of 100 mg/m2 on days 1 and 2 every 3 weeks based on the previous results in lymphoma. RESULTS: Bendamustine was well tolerated in spite of heavy pre-treatment of the study participants. Toxicity corresponded to the known safety profile of bendamustine, with the exception of bilirubin elevation. The level of 110 mg/m2 was established as MTD. A bendamustine dose of 100 mg/m2 is the recommended dose for further clinical investigations. A 4-week interval is recommended to allow for sufficient recovery. Efficacy results confirmed powerful anti-neoplastic activity of bendamustine even in extendedly pre-treated CLL patients. Based on the remission criteria, nine patients were defined as responders (four CRs, two PR, three NC) and two patients as nonresponders to therapy. Four patients were not evaluable for response, because they had received less than three courses bendamustine. After a follow-up period of 15 months, the four patients with CR were still in remission. One patient with PR had relapsed, the other had ongoing response. CONCLUSIONS: Bendamustine is a very active and well-tolerated drug in patients with pre-treated and refractory CLL. Fludarabine-naivity of patients appears to markedly improve their bendamustine tolerability. First-line use of bendamustine is a safe option for CLL-patients requiring treatment, because bendamustine-owing to its unique pharmacodynamics-(1) is highly effective, (2) reasonably safe, and (3) does hardly produce cross-resistance against other anti-neoplastic drugs effective in this indication.

Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC.

Two i.v. regimens, bendamustine, methotrexate and 5-fluorouracil (BMF) and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) were compared as first-line therapy in a randomized, open, multicenter phase III trial including 364 patients with metastatic breast cancer (MBC). Bendamustine is an anti-neoplastic agent with alkylating, but also additional, so far unclear, mechanisms of action. We wanted to show the superiority of BMF over CMF in terms of time to progression (TTP) (primary endpoint), overall response, response duration, toxicity and quality of life (QoL). TTP was significantly longer in the BMF group (8.2 versus 6.7 months for CMF) (p=0.0071). The effect of BMF on TTP was more pronounced in the stratum 'prior adjuvant therapy, no visceral metastases' (p=0.034). Overall response rates and QoL did not significantly differ between the regimens. BMF caused more mucositis and leukopenias. Thus, bendamustine, when replacing cyclophosphamide in the CMF combination, can be expected to produce longer progression-free survival in first-line treatment of MBC.

[Comparative morphological studies of cervix cancer and adjacent tissue following preoperative intracavitary contact therapy using Cf-252 or Co-60]. / Vergleichende morphologische Untersuchungen des Zervixkarzinoms und benachbarter Gewebe nach präoperativer intrakavitärer Kontakttherapie mit Cf-252 bzw. Co-60.

The effects of Cf-252 and Co-60 radiation have been compared by investigating radiation response and radiation pathomorphosis of the cervical carcinoma and surrounding normal tissue. The effectiveness of radiotherapy treatment was evaluated by comparison of Cf-252 and Co-60 irradiated patients (each arm 18 patients) with a non-irradiated control group (15 patients), suffering from epithelium carcinomas of the cervix uteri. The total dose in point A was 60 isoGy in either case given in 3 fractions at 28 days using the after-loading units "ANET" (neutrons) and "AGAT V" (gamma). Two to three weeks after irradiation, extended extirpation of the uterus and its adnexa was performed. The therapeutic effect was strongest in both comparative groups with superficially located exophytic forms of the cervical carcinoma and with carcinoma in situ. With invasive growth forms, signs of therapeutic pathomorphosis were found in both groups predominantly in the superficial tumor areas. However, the extent of the remaining tumor complexes was much greater with Co-60 than with Cf-252 radiation. Adenocarcinomas were more sensitive to Cf-252 independently of the invasion depth of the tumor. The observed alterations in the surrounding normal tissue of the uterus, both in the immediate proximity of the Cf-252 source (endometrium) and at some distance (myometrium, perimetrium) reflect the more severe alterations following irradiation as compared with Co-60. The lower values of the volume density of the tumor parenchyma remaining after radiotherapy and the high damage index (95.5%) give evidence for the pronounced biological and therapeutic effectiveness of high dose rate Cf-252-radiation. They allow to expect improvement of late results in the treatment of patients with epithelium carcinoma of the cervix uteri, and it seems to be reasonable to make further studies in that direction.