fibrinopeptide-a and Carcinoma--Small-Cell

Small cell carcinoma of the lung (SCCL) responds commonly to combination chemotherapy but resistance to therapy follows. Prior reports have suggested that a relationship may exist between plasma fibrinogen levels and response to therapy in SCCL. This study was designed to determine the possible predictive value of the fibrinogen level for tumor response (chemoresistance) in SCCL. Pretreatment fibrinogen levels were correlated with outcome and response to therapy in a cohort of 119 previously untreated patients with SCCL who were admitted to VA Cooperative Study 188. Higher pretreatment fibrinogen levels at diagnosis correlated significantly with more advanced stage of disease at entry (P < 0.001) and with reduced overall survival (P = 0.030). In addition, higher pretreatment fibrinogen levels were correlated significantly with a reduced likelihood of achieving subsequent disease regression with combination chemotherapy (P = 0.005). Because several clinical trials have shown that anticoagulant therapy improves tumor response rates and survival of SCCL, we postulate that tumor cell thrombin generation not only promotes SCCL growth but may also be primarily responsible for both increased fibrinogen levels and for resistance to chemotherapy. These findings provide incentive for studies of thrombin effects on the development of multidrug resistance, and for new clinical trials of more potent and specific inhibitors of thrombin that may further improve tumor response and survival in SCCL.

Topics: Carcinoma, Small Cell; Cohort Studies; Drug Resistance; Fibrinogen; Fibrinolysin; Fibrinopeptide A; Fibrinopeptide B; Humans; Lung Neoplasms; Mopidamol; Randomized Controlled Trials as Topic; Regression Analysis; Thrombin

Disorders of haemostasis and altered platelet activity have been documented in patients with malignant disease but their relation to response to treatment and prognosis are not known. Thrombin activity (fibrinopeptide A (FpA), plasmin mediated fibrinolysis (B beta 15-42) antigen), and platelet alpha granule release (beta thromboglobulin) were studied in 37 patients with small cell lung cancer to find out whether these indices show a relationship to chemoresponse. There was evidence of considerably increased thrombin activity, with a median fibrinopeptide A concentration of 13.2 (normal less than 4) pmol/ml, but only modestly increased fibrinolysis, with a median B beta 14-42 antigen concentration of 5.6 (normal less than 3) pmol/ml. Thus the ratio of fibrinopeptide A to B beta 15-42 concentration (FpA:B beta) was raised, with a median value of 2.2 (normal less than 1.33). In addition, 57% of patients had increased platelet alpha granule release, the median beta thromboglobulin concentration being 50 (normal less than 50) ng/ml. There was a significant association between increased thrombin generation and lack of response to chemotherapy. Furthermore, non-responders had higher FpA:B beta ratios. The same haemostatic markers were studied in nine patients who have been in complete remission for at least two years after chemotherapy for small cell lung cancer. There was a significant difference in thrombin activity and also in the ratio of thrombin activity to lysis between the pretreatment group and the group of two year survivors. Lack of response to chemotherapy appears to be related to increased thrombin activity. Such an association has not previously been reported in patients with malignant disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta-Thromboglobulin; Blood Platelets; Carcinoma, Small Cell; Fibrinolysis; Fibrinopeptide A; Hemostasis; Humans; Lung Neoplasms; P-Selectin; Platelet Membrane Glycoproteins

Hemostatic analyses were carried out on 43 patients with small and non-small cell lung cancer, malignant lymphomas and plasmacytomas prior to, 4 h and 24 h after application of chemotherapy. The fibrinopeptide A (FPA) level and the FPA in vitro generation rate (delta FPA) increased significantly only in the small cell lung cancer and malignant lymphomas after 4 h. This supports the thesis of the clotting activation after cytostatic-induced exposition of the tumour cell thromboplastins. An increase in the FPA was observed in those tumor patients, where a high therapy-induced cell destruction was expected. An increase in the activity of factor VIII, as was seen in acute phase reactions, also led to hypercoagulability. Fibrinogen and plasminogen decreased significantly after chemotherapy. Evidence of relevant contact activation was not found in the missing deviation of the C1 inhibitor. The increase in protein C may possibly be attributed to the high-dose corticoid therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Fibrinogen; Fibrinopeptide A; Hodgkin Disease; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Plasmacytoma