CLINICAL-VALUE OF EXTENDED BIOLOGIC STAGING BY BONE-MARROW MICROMETASTASES AND TUMOR-ASSOCIATED PROTEASES IN GASTRIC-CANCER

Objective To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic information on patients with curatively resecte d gastric cancer. Background Tumor-associated proteolytic mechanisms h ave been shown to be essential for invasion and metastasis. The urokin ase-type plasminogen activator (uPA) system is of major biologic impac t, but different interactive proteases and inhibitors with modulating effects also must be considered. The detection of early tumor cell dis semination indicates the systemic character of a primarily local gastr ic cancer. The confrontation of the organism with these cells determin es the often unpredictable course of an individual tumor after presume d curative primary treatment. Methods In a prospective study of 247 co nsecutive patients with gastric cancer, detection of disseminated tumo r cells in bone marrow aspirates was immunocytochemically performed in 180 patients. The expression of uPA, activators of uPA (cathepsin D, antithrombin III), uPA substrates (plasminogen, matrix-metalloproteina se 2 [collagenase IV, 72 kD; MMP-2]), uPA/plasmin inhibitors (plasmino gen activator inhibitor type 1 and 2 [PAI-1, PAI-2], alpha 1-antitryps in, alpha 2-antiplasmin), uPA receptor (uPA-R), and parameters of the uPA-R cycle (alpha 2-macroglobulin, alpha 1-antichymotrypsin) could be determined immunohistochemically and were scored semiquantitatively i n 203 patients. Kaplan-Meier statistical techniques and multivariate C ox regression models were used for prognostic analyses. Results In mul tivariate analysis considering all the established risk factors, disea se-free survival was independently predicted by PAI-I (relative risk 2 .21, 1.32-3.73) and cathepsin D (relative risk 2.98, 1.28-6.91) beside s pT, pN, and extended resection. Tumor cell dissemination was found t o be an additional prognostic factor in early tumor stages (pT1, T2) a nd lymphnode-negative patients. Stepwise regression analysis revealed an extended staging system with new risk groups. Node-positive, curati vely resected pT1/2 patients with low expression of PAI-I had a favora ble prognosis (mean recurrence-free survival [MRT] 54.84 months), simi lar to that of node-negative patients (MRT 54.76 months). in node-nega tive, curatively resected pT1/2 patients, detection of bone marrow tum or cells and high expression of PAI-1 defined a subgroup with a steep decrease of prognosis (MRT 36.60 months), which was worse than that of node-positive patients (MRT 45.81). Conclusion This new staging model gives better prognostic differentiation of subgroups, which should be considered in future adjuvant therapy protocols. In addition, it indi cates that the uPA system might be a future therapeutic target.