Chemotherapy-induced activation of hemostasis: effect of a low molecular weight heparin (dalteparin sodium) on plasma markers of hemostatic activation.

PURPOSE: To evaluate the effect of standard chemotherapeutic regimens on the hemostatic profile of patients with breast and lung carcinoma; and to evaluate the effect of a single dose of a low molecular weight (LMW) heparin, dalteparin sodium, administered prior to the chemotherapy on markers of hemostatic activation. PATIENTS AND METHODS: 11 patients with breast cancer and 10 patients with lung cancer receiving systemic chemotherapy were studied. 10 breast cancer patients and 9 lung cancer patients completed at least 1 cycle of treatment and had all hemostatic studies. Patients had a complete hemostatic and prothrombotic profile performed at study initiation. Markers of hemostatic activation consisting of immunoassays for thrombin-antithrombin (TAT) complex and D-dimer were measured in plasma samples obtained prior to chemotherapy and at 1, 24 and 48 h after treatment. A 2500 U dose of dalteparin was given prior to the 2nd cycle of chemotherapy; 5000 U of dalteparin was given prior to the 4th treatment cycle. RESULTS: Chemotherapy resulted in statistically significant increases in TAT and D-dimer for the 1, 24 and 48 h plasma samples in both the breast and lung cancer patients for all cycles of chemotherapy given without LMW heparin. There were statistically significant increases in basal thrombin generation over the 4 cycles of treatment which was unrelated to active cancer. Both pretreatment doses of dalteparin effectively prevented increases in the markers of hemostatic activation. However, in the lung cancer patients, who had significantly increased basal thrombin generation, the 5000 U dose dalteparin was more effective. CONCLUSION: Chemotherapy results in significant hemostatic activation in patients with breast and lung cancer. The effect of treatment appears to be cumulative. A single dose of LMW heparin administered prior to therapy can suppress hemostatic activation.

Phase II trial of irinotecan, paclitaxel and carboplatin in patients with previously untreated Stage IIIB/IV nonsmall cell lung carcinoma.

BACKGROUND: This Phase II multicenter, open-label, single-arm study evaluated the efficacy and safety of a three-drug combination of irinotecan (CPT-11), paclitaxel, and carboplatin in advanced nonsmall cell lung carcinoma (NSCLC). METHODS: Patients received repeated 21-day cycles at starting doses of paclitaxel 175 mg/m(2) administered over 3 hours, followed by carboplatin AUC of 5 over 30 minutes and CPT-11 at a starting dose level of 100 mg/m(2) over 90 minutes, all given on the first day of each cycle. Patients were evaluated for objective tumor response, time to tumor progression (TTP), survival, and safety. RESULTS: Forty patients were enrolled. Baseline patient characteristics included: median age 58 years (range, 32-79); 23 males and 17 females; performance status of 0 (21 patients), 1 (18 patients), or 2 (1 patient); and Stage IIIB (10 patients) and Stage IV (30 patients) disease. A median of six cycles (range, one to eight) were administered. Grade 3-4 toxicities observed in >/= 10% of the patients included neutropenia (78%), asthenia (20%), diarrhea (20%), nausea (18%), vomiting (13%), anemia (10%), and dyspnea (10%). Febrile neutropenia occurred in eight patients (20%), with one death due to neutropenic sepsis. Twelve of 38 evaluable patients had confirmed tumor responses (32%), while 21 (55%) had stable disease (including 12 patients [32%] with minor responses). Only 13% had disease progression at their initial tumor assessment. The median TTP and survival were 5.3 months (range, 0.03-6.2 months) and 12.5 months (range 0.3-28.6+ months), respectively. The one and two year survival probabilities were 0.50 (95% confidence interval [CI], 0.28-0.73) and 0.21 (95% CI, 0.0-0.67), respectively. CONCLUSIONS: The combination of CPT-11, paclitaxel, and carboplatin can be safely administered and is active in the treatment of advanced NSCLC. Based on the favorable survival outcome, this regimen is undergoing evaluation in prospective randomized trials.