Intraoperatively administered aprotinin and survival after elective liver resection for colorectal cancer metastasis - A preliminary study

Objective: Local extracellular-matrix degradation by tumour-derived proteol ytic enzymes appears to be a prerequisite for tumour cell invasion. Among t hese enzymes, urokinase-type plasminogen activator (uPA), a serine protease that converts plasminogen into the active protease plasmin, plays a centra l role in tumour invasion and metastasis. Plasmin generation induces extrac ellular proteolysis through direct basement membrane protein degradation an d activation of prometalloproteinases. Neutralization of plasmin activity a nd inhibition of plasmin-generation reduced tumour growth and invasiveness in experimental models. Since circulating tumour cells were detected intrao peratively in patients undergoing hepatectomy for colorectal liver metastas is and since this condition has been suggested to favour metastatic dissemi nation, we checked the hypothesis that intraoperative aprotinin administrat ion, a potent antiplasmin agent, would reduce tumour dissemination and, the refore, improve survival after elective liver resection for cancer. Methods: Thirty-seven consecutive patients undergoing elective liver resect ion for colorectal cancer metastases, exclusively with curative intent, wer e randomly allocated to receive, intraoperatively, either aprotinin or plac ebo. They were a subpopulation of 97 consecutive patients included between December 1992 and August 1995 in a placebo-controlled trial of aprotinin wh ich demonstrated a significant intraoperative blood-sparing effect and a re duction in intraoperative fibrinolysis by aprotinin therapy. The effect of aprotinin on survival rate at 365 days after surgery, on postoperative cumu lative survival on 1 January 1998, on intraoperative fibrinolysis and on in traoperative blood loss were investigated in this homogeneous group of 37 p atients. The correlation between survival rate and the amount of red blood cell (RBC) intraoperatively transfused was tested using linear regression. The effect of repeat surgery on survival was investigated by a Cox model. Results: All patients died of cancer recurrence or metastasis. One year aft er surgery the number of patients still alive was significantly higher in t he aprotinin group than in the placebo group (P = 0.029), This beneficial e ffect on survival was no longer detectable on long-term evaluation (P = 0.0 8 on 1 January 1998). Survival rate was not correlated with the amount of R BC intraoperatively transfused (P = 0.94, R-2 = 0.080), Repeat surgery had no effect on 1 year survival (P = 0.17) and on the overall survival assessm ent (P = 0.24). Conclusion: We suggest that the intraoperative administration of aprotinin hampered early tumour cell invasion by inhibiting intraoperative systemic p lasmin activity associated with cancer cells. Therefore, cancer recurrence was delayed. These data support an additional beneficial effect of aprotini n therapy in addition to the blood-sparing effect.