Antiangiogenic treatment with endostatin inhibits progression of AML in vivo.

Increased vessel density in the bone marrow of patients with acute myeloid leukemia as well as elevated expression of proangiogenic factors by leukemic cells implies a central role of angiogenesis in hematological malignancies. Endostatin (ES), a fragment of collagen XVIII, is an endogenous inhibitor of angiogenesis that has shown therapeutic activity in solid tumors in various preclinical models. Using microencapsulation technology, we studied the therapeutic effect of ES in AML. While ES had no effect on proliferation of M1 murine leukemic cells in vitro, ES producing microbeads significantly inhibited growth of subcutaneous chloromas in SCID mice as compared to controls. In a leukemia model using M1 cells the concomitant treatment of mice with ES microbeads prolonged median survival significantly. Histological analysis revealed a decreased microvessel density and a reduced number of CD31-positive single cells, putatively endothelial progenitor cells, in the bone marrow of treated animals. Taken together, ES has inhibitory effects on neo-angiogenesis in the bone marrow and on progression of leukemia in vivo. These experiments suggest a possible therapeutic role of antiangiogenic gene therapy with ES in AML.

Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group.

PURPOSE: To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between September 1999 and June 2001, 300 patients with NSCLC stage IIIB with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 + cisplatin 75 mg/m(2) on day 2 every 3 weeks). Primary end point of the study was overall survival. RESULTS: Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P =.73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P =.35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P =.004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed. CONCLUSION: In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated.

Pretreatment serum levels of matrix metalloproteinase-9 and vascular endothelial growth factor in non-small-cell lung cancer.

BACKGROUND: Matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF) are two proteins involved in angiogenesis. In the present study we investigated the association of pretreatment MMP-9 and VEGF serum levels with clinicopathological parameters and outcome in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: From February 1998 to October 1999, pretreatment serum levels of MMP-9 and VEGF were analysed in 118 patients with enzyme-linked immunoassays. At diagnosis 50 patients (42%) were staged as early disease (I/II), 27 patients (23%) as locally advanced (IIIA/IIIB), and 41 patients (35%) had metastatic disease (IV). In 72 of the 118 patients tumours were resected and 46 patients received combination chemotherapy with gemcitabine and vinorelbine. RESULTS: The median survival of all 118 patients was 602 days. The 72 patients who had undergone surgery had a median survival of 972 days and the 46 patients who were treated with chemotherapy had a median survival of 298 days (P <0.001). Resected patients with stage I/II disease and an MMP-9 serum level

IgM myeloma: a report of four cases.

IgM myeloma is a rare disease, accounting for approximately 0.5% of multiple myelomas (MM). Here we report four cases of IgM multiple myeloma. Two were diagnosed in advanced clinical stages with multiple osteolytic lesions, leading to hypercalcemia in one patient. Bone marrow morphology showed a variable degree of infiltration with mainly mature plasma cells. An immunophenotypic analysis performed in one case showed expression of CD38 and monoclonal cytoplasmatic immunoglobulin. Interphase fluorescence in situ hybridization performed in one case did not reveal any aneuploidies or deletions of the retinoblastoma, P16, or P53 tumor suppressor genes. While one patient with a smoldering IgM myeloma did not need specific therapy, the others received cytotoxic treatment based on standard chemotherapy for MM. The outcomes were one stable disease, one sustained complete remission, and one progressive disease. All four patients were alive 1 year after diagnosis. One died due to progressive disease after 31 months. We conclude that IgM myeloma shares clinical and histological features with other MM rather than with Waldenström's macroglobulinemia, which is most commonly diagnosed in cases with IgM monoclonal gammopathy. Since MM and Waldenström's macroglobulinemia differ in prognosis and treatment strategies, the two disease entities should be distinguished based on clinical criteria, bone marrow morphology, and immunophenotypic analysis.

Gemcitabine, vinorelbine and cisplatin combination chemotherapy in advanced non-small cell lung cancer: a phase II trial.

The purpose of this phase II trial was to investigate the efficacy and safety of a combination chemotherapy with gemcitabine, vinorelbine and cisplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Patients with NSCLC stage IIIB or IV disease received 1000 mg/m(2) gemcitabine and 25 mg/m(2) vinorelbine on days 1 and 8 and 75 mg/m(2) cisplatin on day 2, every 3 weeks. From December 1998 to May 1999, 31 patients (21 stage IV and 10 stage IIIB disease), with a median age of 59 years (range 40-72 years) were enrolled. The overall intent-to-treat response rate was 45% (95% confidence interval (CI): 27-64%) with 2 complete responders (CR) and 12 partial responders (PR), 7 patients had stable disease and 10 progressed. Median survival was 12.8 months (95% CI: 6.5-12.8+ months), median time to progression was 5.1 months (95% CI: 3.5-7.7 months), and the 1-year survival rate was 52.9% (95% CI: 36.7-76.2%). Patients with stage IIIB disease had a significantly longer overall survival than patients with stage IV disease (P=0.05). Transient World Health Organization (WHO) grade IV leucopenia, anaemia and thrombocytopenia occurred in 3 (10%), 2 (6%) and 3 (10%) patients, respectively. The predominant non-haematological toxicities were alopecia and nausea/vomiting. 15 patients (48%) had WHO grade II and III alopecia and 14 patients (45%) nausea/vomiting. The combination of gemcitabine, vinorelbine and cisplatin has demonstrated major antitumour efficacy in advanced NSCLC with a manageable toxicity profile.

Gemcitabine and vinorelbine as first-line chemotherapy for advanced non-small cell lung cancer: a phase II trial.

The purpose of this phase II study was to investigate the efficacy and safety of gemcitabine plus vinorelbine as first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), no previous chemotherapy, and bidimensionally measurable disease. Patients received 1000 mg/m(2) gemcitabine and 30 mg/m(2) vinorelbine on days 1, 8 and 15 every 4 weeks up to eight courses. From December 1997 to November 1998, 70 patients (59 stage IV and 11 stage IIIB disease), with a median age of 59 years (range 38-74 years) were enrolled. The intent-to-treat response rate was 41% (95% confidence interval (CI) 30-54%) with 1 complete responder (CR) and 28 partial responders (PRs), 15 patients had stable disease (SD) and 26 progressed (PD). Median survival was 8.3 months (95% CI 6.0-9.9 months), median progression-free survival (PFS) was 4.8 months (95% CI 3.9-5.5 months), and 1-year survival rate was 33.5% (95% CI 24.0-46.8%). Patients received a total of 229 cycles. Haematological and non-haematological toxicities were moderate. Transient World Health Organization (WHO)-grade IV leucopenia and thrombocytopenia occurred in 13 (6%) and two (1%) cycles, respectively. The predominant non-haematological toxicity was local reactions of the veins in 19 (27%) patients (WHO-grade II and III). Neurotoxicity was infrequent, non-cumulative, and reversible. The combination of gemcitabine and vinorelbine has demonstrated activity in metastatic NSCLC, with response and survival rates similar to those of cisplatin-based regimens and a more favourable toxicity profile that is well tolerated in an outpatient setting.

A clinical trial of edrecolomab, interleukin-2 and GM-CSF in patients with advanced colorectal cancer.

Immunological effector mechanisms of monoclonal antibodies such as antibody-dependent cytotoxicity can be augmented by the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2). Therefore twelve patients with metastatic colorectal cancer were treated with 300 microg GM-CSF and 6 million units IL-2 subcutaneously daily from day 1 to 10 followed by a three week rest period. Of the edrecolomab 400 mg was given on day 3 of the first cycle. The dose was reduced to 150 mg on subsequent cycles. A maximum of four cycles was administered. Toxicity was manageable on an outpatient basis. No partial or complete responses were observed in these 12 patients. Median time to treatment failure was 67 days and median survival 287 days. Immunological parameters were monitored throughout the study.

Hand-foot syndrome associated with short infusions of combination chemotherapy with gemcitabine and vinorelbine.

The hand-foot syndrome (palmar-plantar erythrodysesthesia) is a side-effect which is associated with several cytotoxic agents (e.g. 5-fluorouracil, UFT, capecitabine, cytarabine, doxorubicin, liposomal-encapsulated doxorubicin). An association with a prolonged infusion of high doses of vinorelbine has also been described. To date a hand-foot syndrome after gemcitabine or short infusions of vinorelbine has not been reported before. The patient described here had a non-small-cell lung cancer stage IIIB disease and developed a hand-foot syndrome after short infusions of standard-dose chemotherapy of a combination with gemcitabine and vinorelbine.