A phase II randomised (calibrated design) study on the activity of the single-agent trabectedin in metastatic or locally relapsed uterine leiomyosarcoma.

BACKGROUND: Patients with recurrent/metastatic uterine leiomyosarcoma (U-LMS) have a dismal prognosis. This phase II study aims to evaluate trabectedin efficacy and safety in advanced U-LMS. METHODS: Eligible patients had received ≥ one line of chemotherapy. Gemcitabine ± docetaxel naive patients were randomised to Arm A: trabectedin 1.3 mg/m2 or calibration Arm B: gemcitabine 900 mg/m2 and docetaxel 75 mg/m2. Patients who had already received gemcitabine ± docetaxel directly entered Arm A. Primary end-point: 6-month progression-free rate (PFS-6). The null hypothesis that the true PFS-6 = 14% was tested against a one-sided alternative. This design yielded a 5% type I error rate and 90% power when the true PFS-6 is 25%. RESULTS: Overall, 126 patients entered Arm A (45 from randomisation and 81 directly) and 42 Arm B. Arm A patients characteristics: median age = 57; ≥2 previous chemotherapy lines = 37.4%; metastatic disease = 93%. The study met the condition for trabectedin activity: PFS-6 = 35.2% (95% CI: 26.2-45). No difference in PFS by the number of previous chemotherapy lines emerged. Median OS = 20.6 months (IQR: 8-36.4). In Arm B, the PFS-6 = 51.5% (95% CI: 33.5-69.2). No toxic deaths occurred. In Arm A, only 4 patients interrupted treatment for toxicity. CONCLUSIONS: Trabectedin is active and well tolerated, retaining similar efficacy across one to three previous lines of chemotherapy.

Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors.

Activated leukocyte cell adhesion molecule (ALCAM) is involved in cell-cell interactions in cancer. Shedding of its ectodomain by the metalloprotease ADAM17/TACE generates a soluble form (sALCAM). Here, we show that serum sALCAM levels were significantly higher in epithelial ovarian cancer (EOC) (p < 0.005) than in controls. The performance of sALCAM as classifier, tested by receiver operating characteristic curve, resulted in an area under the curve (AUC) of 0.8067. Serum sALCAM levels showed direct correlation with Carbohydrate Antigen-125 (CA125/MUC16). Moreover, significantly higher levels were found in type II tumors, even in stage I/II, suggesting that elevated sALCAM is an early feature of aggressive EOC. In addition, sALCAM levels were higher in ascites than in sera, suggesting local processing of ALCAM in the peritoneal cavity. In immunodeficient mice, intraperitoneally implanted with a human EOC cell line, human sALCAM progressively increased in serum and was even higher in the ascites. The biochemical characterization of the sALCAM in EOC sera and ascites, showed two predominant forms of approximately 95 and 65 kDa but no EOC-specific isoform. In addition, full-length transmembrane ALCAM but no soluble form was detected in tumor-derived exosomes found in ascites. Finally, in vitro invasion assays showed that inhibition of ADAM17/TACE activity decreased EOC invasive properties, while opposite effects were mediated by a sALCAM-Fc chimera and by an antibody interfering with ALCAM/ALCAM interactions. Altogether these data suggest that sALCAM is a marker of EOC, which correlates with more aggressive type II tumors, and that ADAM17/TACE activity and sALCAM itself mediate enhanced invasiveness.

Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor.

Interleukin (IL)-18 is a proinflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL-18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro-IL-18) in vitro. In addition, IL-18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL-18 is increased in EOC patients' sera at diagnosis as compared with age-matched healthy women. IL-18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL-18 expression in cytokeratine-positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL-18. The detection of human IL-18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL-18 is tumor-derived. However, IL-18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL-18 present in the ascitic fluid as pro-IL-18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL-18 levels. Altogether these data indicate that IL-18 in EOC fluids is predominantly tumor-derived and that its lack of biological activity may represent a mechanism of tumor-escape.

Chemotherapy with cisplatin and 5-fluorouracil chronomodulated infusion in locally advanced or metastatic/recurrent carcinoma of the cervix.

AIMS AND BACKGROUND: The purpose of this study was to review our experience with the combination of circadian chronomodulated 5-fluorouracil infusion in association with cisplatin in patients with locally advanced or metastatic cancer of the cervix in order to assess the activity and tolerability of the combination. METHODS: Twenty patients with locally advanced disease and 21 patients with metastatic or recurrent disease were treated from January 1995 to May 1999. 5-fluorouracil (600 mg/m2, days 1 to 5) was administered by a continuous circadian-shaped infusion employing an external programmable portable pump; cisplatinum (20 mg/m2) was infused days 1 through 5 i.v. over a 2-hr period. Response to treatment was evaluated after 3 and 6 cycles of therapy. Patients with locally advanced disease who achieved a clinical shrinkage of their tumor or were at least stable were submitted to surgery; pelvic radiotherapy was administered to patients with disease progression. RESULTS: Seven patients with locally advanced disease achieved a partial clinical response (overall response, 35%; 95% CI, 15.4-59.2), and 12 of 20 patients were submitted to surgery. Median progression-free and overall survival were 17 months and 36 months, respectively. Objective responses were observed in 9 of 21 patients with metastatic/recurrent disease (7 partial plus 2 minor responses: overall response 43%; 95% CI, 21.8-65.9). Median time to progression and overall survival were 5 and 17 months, respectively. CONCLUSIONS: Cisplatinum plus 5-fluorouracil chronomodulated infusion showed a moderate but definite activity and was well tolerated in both groups of patients. In consideration of clinical results comparable to more toxic and expensive regimens reported in the literature, the combination appears to be a reasonable option especially for women with metastatic/recurrent cervical carcinoma and a promising treatment in combination with definitive radiotherapy in patients with locally advanced disease.