Long-term survival results for patients with locally advanced, initially unresectable non-small cell lung cancer treated with aggressive concurrent chemoradiation.

PURPOSE: Patients with locally advanced, initially unresectable non-small cell lung cancer (NSCLC) have a median survival time of 9 to 11 months, a 2-year survival rate of 13%, and a long-term survival rate of 5% to 7% when treated with radical thoracic radiation alone. Because of the preclinical radiosensitizing capabilities of 5-fluorouracil and cisplatin and the therapeutic synergy of etoposide and cisplatin, we combined these agents with full-dose radical thoracic radiation to determine the feasibility and efficacy of this approach in locally advanced NSCLC. METHODS: Patients with clinical stage IIIb and bulky IIIa NSCLC and ECOG performance status 0 or 1 received 5-fluorouracil infusion (640-800 mg/m2/d CVI days 1-5, 29-34), cisplatin (20 mg/m2/d, days 1-5, 29-34), etoposide (50 mg/m2, days 1, 3, 5, 29, 31, 33) and concurrent thoracic radiation (60 Gy/2 Gy/d/30 Fx). Patients with adequate cytoreduction proceeded to surgical resection. RESULTS: From March 1987 to July 1990, 41 patients were enrolled on study; 40 are evaluable. The objective response rate was 90%. Thirteen patients (39%), five with clinical stage IIIb disease and eight with IIIa disease, underwent thoracotomy and resection; three proved to have pathological complete remissions. Ten of 77 chemotherapy courses were complicated by neutropenic fever. Grade 3 or 4 esophagitis occurred in 21 patients (52%). Cardiac ischemia or infarction occurred in two patients (5%). There were seven deaths in the first 6 months in the absence of disease progression. Two-year survival was 38%, 3-year survival 25%, and 4- to 5-year survival 18%. Six patients (15%) remain alive at the median follow-up time of 66 months (range, 64-84). CONCLUSIONS: Despite substantial early morbidity and mortality, concurrent, aggressive chemoradiation produced a long-term survival rate in locally advanced NSCLC comparable to other combined modality approaches. However toxicity, particularly esophagitis and postoperative complications, preclude the use of this regimen in phase III studies. Combined modality approaches for locally advanced, initially unresectable NSCLC have become standard; research must simultaneously focus on ways to enhance efficacy and reduce toxicity.

Regulation of factor XIa activity by platelets and alpha 1-protease inhibitor.

We have studied the complex interrelationships between platelets, Factor XIa, alpha 1-protease inhibitor and Factor IX activation. Platelets were shown to secrete an inhibitor of Factor XIa, and to protect Factor XIa from inactivation in the presence of alpha 1-protease inhibitor and the secreted platelet inhibitor. This protection of Factor XIa did not arise from the binding of Factor XIa to platelets, the presence of high molecular weight kininogen, or the inactivation of alpha 1-protease inhibitor by platelets. The formation of a complex between alpha 1-protease inhibitor and the active-site-containing light chain of Factor XIa was inhibited by activated platelets and by platelet releasates, but not by high molecular weight kininogen. These results support the hypothesis that platelets can regulate Factor XIa-catalyzed Factor IX activation by secreting an inhibitor of Factor XIa that may act primarily outside the platelet microenvironment and by protecting Factor XIa from inhibition, thereby localizing Factor IX activation to the platelet plug.