ANGIOGENESIS AS A PROGNOSTIC INDICATOR OF SURVIVAL IN NON-SMALL-CELL LUNG-CARCINOMA - A PROSPECTIVE-STUDY

Background: Tumors acquire nutrients that are essential for continued growth and an avenue for dissemination to the rest of the body by indu cing angiogenesis (i.e., the formation of new blood vessels). Prelimin ary studies involving a number of different kinds of cancer have indic ated that an assessment of tumor angiogenesis may be useful in predict ing disease outcome. Purpose: In a prospective study, we evaluated the relationship between tumor angiogenesis and survival for 407 patients with nonsmall-cell lung carcinoma who were treated with potentially c urative surgery. Methods: The study population consisted of 360 male a nd 47 female patients who underwent surgery consecutively at the Depar tment of Surgery. University of Pisa, Italy, from March 1991 through D ecember 1994. Followup lasted through February 1996, with a median fol low-up for living patients of 29 months (range, 15-60 months). An anti -CD34 monoclonal antibody, which is specific for endothelial cells, an d standard immunohistochemical techniques were used to measure angioge nesis in tumor samples. Angiogenesis was quantified in terms of microv essel counts; the counts for single, high-power microscopic fields (ma gnification x250) in the three most intense areas of blood vessel grow th for each sample were averaged. The median microvessel count in this series was 20, and the counts were categorized as follows: 1) low ver sus high (less than or equal to 20 versus >20 microvessels) or 2) in f ive categories (1-10, 11-20, 21-30, 31-40, and greater than or equal t o 41 microvessels). Disease-free and overall survival during follow-up were assessed. Kaplan-Meier survival curves were modeled in a univari ate analysis of patient and tumor characteristics; the Cox proportiona l hazards model was used in multivariate analysis. Reported P values a re two-sided. Results and Conclusions: In the univariate analysis, pat ients with larger tumors (P for trend <.00001), a more advanced tumor stage (P for trend <.00001), a greater degree of regional lymph node i nvolvement (P for trend <.00001), or more vascularized tumors (high ve rsus low microvessel count, P<.00001) experienced significantly reduce d overall survival. When microvessel counts were analyzed in five cate gories, a highly significant trend (P<.00001) toward worse prognosis w as observed with increasing tumor vascularity. In multivariate analysi s, tumor microvessel count (P<.00001), tumor size (P = .0006), and reg ional lymph node status (P<.00001) retained independent prognostic val ue with respect to overall survival; among these variables, tumor micr ovessel count, considered as a continuous variable, was the most impor tant, with a relative hazard of death of 8.38 (95% confidence interval = 4.19-16.78) associated with the highest microvessel counts. Implica tions: An evaluation of tumor angiogenesis may be useful in the postsu rgical staging of patients with non-small cell lung carcinoma and in i dentifying subsets of patients who may benefit from different postsurg ical treatments.