Urokinase combination chemotherapy in small cell lung cancer. A phase II study

Abstract

Background and Methods. Fifty‐one patients with small cell lung cancer (SCLC) were treated with alternating urokinase (UK)‐cyclophosphamide‐doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)‐vincristine and cisplatin‐etoposide‐vincristine. UK was given as a loading dose of 3000 μg/kg body weight, followed by 3000 μg/kg/h for 6 hours. Thoracic irradiation with split technique (46 Gy) and prophylactic cranial irradiation (25 Gy) were administered to responding patients. A second staging was performed in patients exhibiting a clinical complete response (CR) after 1 year. Results. In 27 patients with limited disease, there were 23 CR and 8 partial responses (PR) (CR, 85.1%; 66.2‐95.8% at 95% confidence intervals); in 24 patients with extensive disease, there were 17 CR, 4 PR, and 3 cases with progression. Pathologically proven CR were observed in 59.2% patients with limited disease and 33.3% patients with extensive disease. Survival rates were as follows: in patients with limited disease, 1 year, 85.1%; 2 years, 55.5%; and 3 years, 25.9%; in patients with extensive disease, 1 year, 54.1; and 2 years, 16.9%. Median survival times were 26.3 months (patients with limited disease) and 13.3 months (patients with extensive disease). UK‐related toxic effects included four episodes of mild to moderate bleeding, one allergic reaction, and one cerebro‐vascular accident. Myelotoxicity was severe, with a median of two episodes of Grade III‐IV (World Health Organization classification) aplasia per patient. Conclusions. These results are consistent with a potential benefit of fibrinolytic therapy in combination with chemotherapy in patients with SCLC with limited disease. Additional trials are indicated.

Fibrinolytic Enzyme Cotherapy Improves Tumor Perfusion and Therapeutic Efficacy of Anticancer Nanomedicine

“…The clinical use of anti-coagulants and fibrinolytic therapies in cancer patients has been reported before (41–45). These studies have shown that administration of anti-coagulants such as heparin and warfarin improve mean survival in patients with small cell lung cancer.…”

“…The rationale presented for the use of anti-coagulants is that it reduces the occurrence of spontaneous thromboembolism and tumor cell dissemination (44, 46). Some studies have reported the beneficial effects of using urokinase in conjunction with chemotherapy (41). The mechanism for the improved response to chemotherapy was not explored, however.…”

Coagulation and cancer: Implications for diagnosis and management

“…94,96 Experimental and clinical studies suggest that heparin and vitamin K antagonists are effective compounds for the prevention of metastases. 33,107 Data from randomised trials suggest that small-cell lung cancer (SCLC) consistently responds to heparin and vitamin K antagonist, but several other tumors, including non small-cell cancer (NSCLC), colon and prostate cancer, do not respond to warfarin 13,11,55,111,117 and do not produce thrombin. 118 Further studies are needed to confirm the existing data and to determine whether haparin, vitamin K antagonists or platelet aggregation inhibitors effectively prevent the formation of metastatic tumors.…”

A randomized clinical trial of combination chemotherapy with and without low‐molecular‐weight heparin in small cell lung cancer

“…Several studies have suggested that anticoagulant therapy may improve survival in patients with SCLC [7]. Specifically, improved SCLC disease outcome has been observed in randomized clinical trials (RCTs) of warfarin [8,>9] and unfractionated heparin [10], and in a Phase II study of urokinase [11]. However, further clinical studies are needed to define the role that anticoagulants will play, if any, in the treatment of SCLC and other tumor types.…”