Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. The serine protease urokinase-type plasminogen activator (uPA), which is elevated in solid tumors, appears to play a key role in these processes. We used enzyme-linked immunoassays (ELISA) to test for uPA antigen and its inhibitor PAI-1 in tumor tissue extracts of 247 breast cancer patients who were enrolled in a prospective study. The relation of these data to known prognostic factors and to other variables such as DNA analysis and cathepsin D was studied. Disease-free and overall survival were analyzed according to Cox's proportional hazard model. The major new finding is that breast cancer patients with either high uPA (> 2.97 ng/mg protein) or high content of the uPA inhibitor PAI-1 (> 2.18 ng/mg protein) in their primary tumors have an increased risk of relapse and death. Multivariate analyses revealed uPA to be an independent and strong prognostic factor. The impact of uPA is as high as that of the lymph node status. In node-negative patients the impact of uPA is closely followed by that of PAI-1. Since uPA and PAI-1 are independent prognostic factors, the node-negative patients could be subdivided further by combining these two variables. In this refined analysis, patients whose primary tumors have lower levels of both antigens evidently have a very low risk of relapse (93% disease-free survival at three years) in contrast to patients with high uPA and high PAI-1 (55% disease-free survival at three years). The combination of uPA and PAI-1 in our group of patients with axillary node-negative breast cancer allows us to identify the 45 percent of patients having an increased risk of relapse. Consequently, more than half of the patients had less than a 10% probability of relapse and thus would possibly be candidates for being spared the necessity of adjuvant therapy.

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Background. There is plenty of evidence that survival time associated with advanced ovarian cancer is predominantly related to the amount of residual tumor after primary operation. However, there are only few and inconclusive reports concerning the effect of second debulking procedures on survival time after relapse. Methods. To evaluate the effect of radical second operation, 30 patients with clinically diagnosed relapses had second operations after a median recurrence‐free interval of 16 months, considerable efforts were made to resect all tumor tissue. Complete resection was achieved in 14 of 39 (47%) patients, and residual tumors smaller than 2 cm remained in 12 (40%) patients. In 19 (63%) patients, intestinal resections were necessary. Operation time, blood units needed, hospital stay, and complication rates were comparable to those associated with primary debulking procedures. Results. Survival time after second operation was closely correlated with the residual tumor remaining after second surgical procedure and also with the length of the recurrence‐free interval. Patients with complete resections had significantly longer survival times than those with residual tumors of less than 2 cm (median, 29 months versus 9 months; P = 0.004). Patients with a recurrence‐free interval of more than 12 months had a longer survival time than those with a shorter disease‐free time (median, 29 months versus 8 months; P = 0.002). Postoperative treatment also was shown to influence survival time, whereas grade of the tumor (P = 0.74), age of the patient (P = 0.87), and initial FIGO stage (P = 0.58) had no influence on survival time after second operation. Multivariate analysis (Cox regression) revealed that residual tumor after second surgical procedure (relative risk, 4.7) was the most important independent variable predicting survival time after second surgical procedure. Recurrence‐free interval (relative risk, 2.7) and postoperative (second‐line) treatment (relative risk, 3.0) were equally potent variables. Residual tumor after primary operation, was almost significant (P = 0.06) in the univariate analysis, but was canceled in the multivariate setting by the recurrence‐free interval. Again, FIGO stage, grade of the tumor, and patient age had no predictive value. Conclusions. The authors conclude that radical surgical procedure can prolong survival times in patients with recurrent ovarian cancer. Patients who had a complete resection of cancer tissue in the primary operation or those who experienced a disease‐free interval of more than 12 months after primary operation are most likely to benefit from second operation in recurrent ovarian cancer. Radical surgical procedure should be offered to these patients to enhance efficacy of second‐line chemotherapy, which is of limited value in bulky recurrent disease.

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Summary Strong evidence has accumulated on the prognostic value of tumour-associated proteolytic factors in patients afflicted with solid malignant tumours, including advanced ovarian cancer. We evaluated the prognostic impact of the protease urokinase plasminogen activator (uPA) and its inhibitor PAI-1 on overall survival in patients with advanced ovarian cancer stage FIGO IIIc in order to select patients at risk. uPA and PAI-1 antigen were determined by ELISA in primary tumour tissue extracts of 86 ovarian cancer patients FIGO stage IIIc enrolled in a prospective study. Univariate and multivariate analyses were performed using the Cox proportional hazard model. The time-varying coefficient model of Gray was used to assess the time-dependent strength of prognostic factors tumour mass, uPA and PAI-1 on overall survival. In all patients, uPA and PAI-1 (optimized cut-offs of 2.0 and 27.5 ng mg -1 protein respectively), in addition to the traditional prognostic parameters of residual tumour mass, nodal status, grading and ascites volume, were of prognostic significance in univariate analysis for overall survival. Even in patients with residual tumour mass (n = 43), the statistically independent prognostic impact of PAI-1 persisted, allowing further discrimination between low-and high-risk patients. In multivariate analysis, residual tumour mass (P < 0.001, relative risk (RR) 4.5), PAI-1 (P < 0.001; RR 3.1) and nodal status (P = 0.022, RR 2.6) turned out to be strong, statistically independent prognostic parameters. Evaluation of the time-dependent prognostic impact of residual tumour mass and PAI-1 on overall survival (n = 86, 50 months) revealed that the prognostic power of these factors increased with time. In patients with advanced ovarian cancer, both residual tumour mass and PAI-1 are statistically independent strong prognostic factors. Even within patient subgroups with or without residual tumour mass, PAI-1 allowed selection of patients at risk who might benefit from individualized therapy protocols.