Association between protein C levels and mortality in patients with advanced prostate, lung and pancreatic cancer.

INTRODUCTION: Procoagulant factors promote cancer progression and metastasis. Protein C is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated protein C reduced experimental metastasis. We assessed the association between protein C and mortality in patients with three types of cancer. METHODS: The study population consisted of patients with advanced prostate, non-small cell lung or pancreatic cancer, who participated in the INPACT trial (NCT00312013). The trial evaluated the addition of nadroparin to chemotherapy in patients with advanced malignancy. Patients were divided into tertiles based on protein C at baseline. The association between protein C levels and mortality was evaluated with Cox proportional hazard models. RESULTS: We analysed 477 patients (protein C tertiles: <97, 97-121 and ≥121%). Mean age was 65±9years; 390 (82%) were male; 191 patients (40%) had prostate cancer, 161 (34%) had lung cancer, and 125 (26%) pancreatic cancer. During a median follow-up of 10.4months, 291 patients (61%) died. Median protein C level was 107% (IQR 92-129). In the lowest tertile, 75 patients per 100 patient-years died, as compared to 60 and 54 in the middle and high tertile, respectively. Lower levels of protein C were associated with increased mortality (in tertiles: HR for trend 1.18, 95%CI 1.02-1.36, adjusted for age, sex and nadroparin use; as a continuous variable: HR 1.004, 95%CI 1.00-1.008, p=0.07). CONCLUSION: Protein C seems inversely associated with mortality in patients with advanced prostate, lung and pancreatic cancer. Further research should validate protein C as a biomarker for mortality, and explore the effects of protein C on progression of cancer.

Performance of the age-adjusted cut-off for D-dimer in patients with cancer and suspected pulmonary embolism.

BACKGROUND: Cancer patients frequently present with suspected pulmonary embolism (PE). The D-dimer (DD) test is less useful in excluding PE in cancer patients due to the lower specificity. In the general population, the age-adjusted cutoff for DD combined with a clinical decision rule (CDR) improved specificity in the diagnosis of PE. OBJECTIVES: To evaluate the safety and efficacy of the age-adjusted cutoff (defined as age∗10µg/L in patients >50years) combined with a CDR for the exclusion of PE in cancer patients. METHODS: We conducted a prospective study to evaluate the age-adjusted cutoff in patients with suspected PE. Here we report a post-hoc analysis on the performance of the age-adjusted cutoff in patients with and without cancer. The primary outcome was the rate of venous thromboembolic events (VTE) during three-month follow-up. RESULTS: Of 3324 patients with suspected PE, 429 (12.9%) patients had cancer. The prevalence of PE was 25.2% in cancer patients and 18% in patients without cancer (p<0.001). Among cancer patients with an unlikely CDR, 9.9% had a DD <500µg/L as compared with 19.7% using the age-adjusted cutoff. In patients without cancer, these rates were 30.1% and 41.9%. The proportion of cancer patients in whom PE could be excluded by CDR and DD doubled from 6.3% to 12.6%. No VTE occurred during three-month follow-up (failure rate 0.0% (95% CI 0.0-6.9%)). CONCLUSION: Compared with the conventional cutoff, the age-adjusted D-dimer cutoff doubles the proportion of patients with cancer in whom PE can be safely excluded by CDR and DD without imaging.

PO-28 - Protein C levels are associated with mortality in patients with advanced cancer.

INTRODUCTION: In cancer, tumor progression and metastasis are promoted by prohemostatic activity. Protein C (PC) is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated PC reduced experimental metastasis. It is unclear whether PC level is associated with mortality in patients with cancer. AIM: To assess the relation between PC level and survival in patients with advanced cancer. MATERIALS AND METHODS: A multicenter, randomized, open-label study was performed in 11 countries between May 2006 and August 2008 (INPACT study, van Doormaal et al, JCO 2011). Patients (n=503) with hormone-refractory prostate cancer, non-small cell lung cancer stage IIIB and locally advanced pancreatic cancer were randomized to receive nadroparin or placebo for 6 to 46 weeks following a specific schedule. Patients were followed till death or the end of the study in May 2009. PC activity levels were measured at baseline and categorized in tertiles. The association between PC level and mortality was evaluated with Cox proportional hazard models, adjustments were made by multivariate Cox proportional hazard models. RESULTS: PC activity could be measured in 479 (95%) patients (tertiles: <97, 97-120 and >120%). Two patients with missing information on type of cancer were excluded. Mean age was 65±10 years; 87 (18%) were female; and 161 patients had lung cancer, 125 pancreatic cancer and 191 prostate cancer. During median follow-up of 10.5 months, 291 (61%) patients died. Median PC activity was 107% (IQR 92-129). There was a clear inverse relation between PC activity and mortality (p for trend=0.036). In the lowest tertile, mortality was 66%, in the middle and high tertile 61% and 56%, respectively. Compared to the highest tertile, the lowest tertile was associated with a HR on mortality of 1.36 (95% CI 1.02-1.80). Adjustment for age, gender and nadroparin use did not affect this association. The association appeared to be strongest in the patients with lung cancer, HR 0.818 (p=0.11) as compared to the patients with prostate cancer, HR 0.972 (p=0.83) and pancreatic cancer, HR 0.950 (p=0.68). CONCLUSIONS: Lower PC activity is associated with increased mortality in patients with advanced cancer. However, validation of our findings in a larger cohort is necessary. When the association of PC and mortality has been proven to be consistent, we would suggest a trial on suppletion of PC in cancer patients.

PO-29 - Age-adjusted D-dimer cutoff level increases the number of cancer patients in who pulmonary embolism can be safely excluded without CT-PA imaging: The ADJUST-PE cancer substudy.

INTRODUCTION: Patients with cancer frequently present with suspected pulmonary embolism (PE). The D-dimer test is less useful to rule out PE in cancer patients due to a lower specificity, whereas the safety of the combination of a clinical decision rule (CDR) and D-dimer test to rule out PE in these patients is unclear. In the general population, use of an age-adjusted cutoff for D-dimer in combination with a CDR has been shown to improve specificity in the diagnosis of PE. AIM: We prospectively analysed the safety and efficacy of the age-adjusted D-dimer (defined as age×10 in patients >50 years) combined with CDR for the exclusion of PE in patients with cancer. MATERIALS AND METHODS: We conducted a multicenter multinational prospective management outcome study in 19 centers in Belgium, France, The Netherlands and Switzerland, the ADJUST-PE study, to validate an age-adjusted D-dimer cut-off in patients with suspected PE. The performance of the age-adjusted D-dimer cut-off and CDR was compared between patients with and without cancer. The primary outcome was the rate of adjudicated thromboembolic events during three-month follow-up. RESULTS: Of the 3,324 patients with suspected PE, 429 (12.9%) patients had cancer. Cancer patients were older and more often had surgery or immobilisation. The prevalence of PE was 108/429 (25.2%) in cancer patients and 522/2894 (18%) in patients without cancer, p<0.001. Among cancer patients with an unlikely CDR, 27/274 (9.9%) had a D-Dimer <500 µg/L as compared with 19.7% using the age-adjusted D-dimer cut-off; in patients without cancer, these rates were 30.1% and 41.9%, respectively. The percentage of cancer patients in whom PE could be excluded based on CDR and age-adjusted D-dimer doubled from 6.3% to 12.6%. None of these cancer patients had a venous thromboembolic event during three-month follow-up, thus the failure rate was 0.0% (95% CI 0.0-6.9%). CONCLUSIONS: Compared with the usual cut-off, the age-adjusted D-dimer cut-off doubles the proportion of patients with cancer in whom PE can be safely excluded by CDR and D-dimer without need for CTPA imaging.