Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma.

PURPOSE: To investigate whether patients with metastatic renal cell carcinoma benefit from sequential therapies with the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib. PATIENTS AND METHODS: A total of 89 patients were treated in nine German centres between 2002 and 2009. The TKI sequence started as first-, second- or third-line therapy after prior chemo- or immunotherapy. When progression was diagnosed, treatment was switched to the second TKI until further progression. RESULTS: Overall progression-free survival (PFS) of patients receiving sunitinib followed by sorafenib shows no statistically significant difference to patients receiving sorafenib followed by sunitinib (15.4 months vs. 12.1 months). The secondary use of sorafenib resulted in a median PFS of 3.8 months if the TKI sequence had been started as a first-line treatment and of 3.5 months if the TKI sequence had been started second-line treatment. The secondary use of sunitinib resulted in a median PFS of 3.4 and 4.0 months, respectively. OS was 28.8 months for all patients, without a statistically significant difference between the two groups. CONCLUSIONS: This study endorses the notion of a clinical benefit of the sequential use of sorafenib and sunitinib and supports observations from previous studies. In terms of the optimal succession of the two TKIs, the study does not allow a definite answer.

[Bendamustine, vincristine, prednisolone (BOP) in therapy of advanced low-grade non-Hodgkin lymphoma]]. / Bendamustin, Vincristin, Prednisolon (BOP) in der Therapie von fortgeschrittenen niedrig malignen Non-Hodgkin-Lymphomen.

BACKGROUND AND OBJECTIVE: Low grade non-Hodgkin lymphomas (l-NHL) are rarely showing complete or sustained remissions to conventional chemotherapy. Thus, many therapeutic strategies try to improve the remission rates and outcome in relapsed and refractory l-NHL. Bendamustine (B) is a non-cross resistant alkylating agent shown to be highly effective in lymphoproliferative and other malignant diseases. In an open phase-II study we evaluated the efficacy and toxicity of B in combination with vincristine (O) and prednisolone (P) in heavily pretreated relapsed or refractory l-NHL. PATIENTS AND METHODS: 22 patients (median age 61.5 years, range 39-77 years) with relapsed or refractory low grade NHL: immunocytoma (IC) n = 11, centroblastic-centrocytic (CB-CC) n = 6, centrocytic (CC) n = 2, others n = 3, were treated with BOP as follows: patients up to 75 years: 60 mg/m2 B for 5 days; patients over 75 years: 50 mg/m2 B for 5 days. All patients received 2 mg vincristine (O) on day 1, 100 mg/m2 prednisolone (P) on day 1-5; repetition day 29. Prior to BOP patients were pretreated with 1-4 chemotherapy protocols. An average of 5 courses of BOP were administered (range 2-8). In most patients BOP was followed by a maintenance therapy (IFN-alpha n = 11, chlorambucil n = 4, etoposide n = 2). RESULTS: Objective remission was achieved in 19/22 (86%) patients, complete remission (CR) in 10/22 (45%), partial remission (PR) in 9/22 (41%) and no change (NC) in 3/22 (14%) patients. The mean duration of remission was 16.1 months. Predominant features of side effects of the BOP protocol were myelotoxicity of WHO grade III/IV in 8 of 109 cycles leukopenia (8%), thrombocytopenia 3 cyles (3%) and anaemia in 4 cycles (4%). We observed one WHO grade IV infectious episode. Other side effects were mild and rare. There was a decline of the CD4/8 in more than 50% of patients. However, these changes were not accompanied by a higher rate of infectious episodes. CONCLUSION: Salvage therapy of refractory and relapsed l-NHL with BOP results in a high objective remission rate. Together with a maintenance therapy most patients achieved a long-term disease-free survival. Myelotoxicity and the inversion of the CD4/CD8 ratio were frequently observed side effects.

Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia.

Bendamustine, an alkylating agent without cross-resistance to cyclophosphamide is active in a variety of lymphoproliferative and other malignancies. In an open phase-II study we treated 23 patients with a median age of 62 years at study entry (43-86 years) with advanced, refractory or relapsed (Rai stage III n = 9, Rai stage IV n = 14) chronic lymphocytic leukemia (CLL) with bendamustine. At study entry, only 13 patients were chemotherapy-naive. The treatment schedule with bendamustine was as follows: for patients up to 70 years 60 mg/m2 for 5 days, for patients over 70 years 50 mg/m2 for 5 days, repetition at day 29. Remission criteria were used according to Cheson et al. (1996). All patients were evaluable for toxicity and 20 for response. An objective remission was achieved in 15/20 patients (75%), including six patients with complete remission (CR). Three of the complete responders had no chemotherapy prior to bendamustine. No change (NC) occurred in 5/20 patients (25%). Median overall survival after bendamustine treatment is 13.6 months (1-46 months) and 16.6 months (1-46 months) in patients responding to bendamustine. In total, 74 courses of bendamustine were applied. Therapy-related anemia and thrombocytopenia were rare. However, WHO grade III/IV leukocytopenia occurred in 38/74 cycles (51%), resulting in treatment-related mortality in 3/23 patients (13%). These patients were severely immunocompromised due to pretreatment or the underlying disease. As a corollary of the study, a general prophylactic antibiotic treatment (trimethoprim/ sulfamerazine) was instituted. A general feature was the decline of the CD4/CD8 ratio: mean before therapy: 1.36; after two courses: 0.98; after four courses: 0.6, as documented in all patients who received at least two courses of bendamustine (n = 12). All evaluable patients showed a decline in the CD4/8 ratio. However, this decline was not clearly related to an increased risk of infectious episodes. We observed mainly cutaneous allergic reactions (three WHO grade I; one WHO grade II) leading to a cessation of bendamustine treatment in 4/23 patients (18%). Bendamustine is highly effective in advanced or refractory CLL. In multiple pretreated or otherwise severely immunocompromised patients bendamustine might lead to additional immunosuppression with subsequent infectious complications.

Correlation between granulocyte/macrophage-colony-forming units and CD34+ cells in apheresis products from patients treated with different chemotherapy regimens and granulocyte-colony-stimulating factor to mobilize peripheral blood progenitor cells.

We examined the efficiency of disease-specific "standard" chemotherapies epirubicin, cyclophosphamide (EC); cyclophosphamide, vincristine, doxorubicin, etoposide, prednisolone (CHOEP); epirubicin, ifosfamide (EPI/IFOS) for peripheral blood progenitor cell (PBPC) mobilization in comparison to well-characterized mobilization protocols, i.e. etoposide, ifosfamide, cisplatin, epirubicin (VIPE) and dexamethasone, carmustine, etoposide, cytarabine, melphalan (DexaBEAM). Twenty-seven patients with various malignancies underwent 75 apheresis procedures for PBPC collection. Median cell yields from all 75 aphereses were 1.18 x 10(5) mononuclear cells/kg [range (0.28-3.7) x 10)8)], 1.4 x 10(5) granulocyte/macrophage-colony-forming units (CFU-GM)/kg [range (0.2-11) x 10(5)] and 3.3 x 10(6) CD34+cells/kg [range (0.35-17.7) x 10(6). CD34+/ CD90+ cells could be mobilized by all mobilization regimens used. The difference observed in the mobilization of CD34+ cells was only of low significance when the mobilization regimens were compared, whereas the mobilizations of MNC and CFU-GM were significantly different between the groups. Breast cancer patients treated with the VIPE regimen (including pretreated women) had a significantly higher CFU-GM rate than patients treated with EC (P=0.0005). Mobilized CD34+ PBPC were correlated with CFU-GM in all apheresis products. The linear correlation coefficients differed for the various mobilization groups: DexaBEAM (r=0.9, P < 0.0001), VIPE (r=0.68, P=0.0024), CHOEP (r=0.52, P=0.022), EPI/ IFOS (r=0.34, P=0.11) and EC (r=0.23, P=0.2). We conclude that clonogenic assays can provide additional information about the autotransplant quality, particularly when alternative or new mobilization regimens are being investigated.

[High dose chemotherapy of solid tumors]. / Hochdosischemotherapie bei soliden Tumoren.

BACKGROUND: The availability of hemopoetic growth factors and the retransfusion of autologous peripheral blood stem cells (PBSC) have enabled high-dose chemotherapy (HDT) options for the treatment of advanced solid tumours, during recent years. Though the transfusion of PBSC can manage the myelosuppression, dose-escalation ist still limited by non-haematological toxicity. METHOD: Usually, HDT has been given after a proceeding dose-intense chemotherapy that allowed the evaluation of chemosensitivity of the disease and resulted in a stem cell mobilization into the peripheral blood. The autologous bone marrow transplantation has almost completely been replaced by retransfusion of PBSC together with hemopoietic growth factors as specific supportive treatment. The PBSC are harvested by apheresis using a blood cell separator. RESULTS: Results on the efficacy of HDT are available for breast, testicular, ovarian, small cell lung cancer as well as melanoma, glioblastoma and soft-tissue sarcoma. The studies showed the feasibility and efficacy of HDT with tolerable toxicity. CONCLUSION: High-dose chemotherapy will be of increasing importance in the treatment strategies of primary solid tumors, in the near future.