Cancer is associated with an increased risk of venous thromboembolism (VTE); the exact mechanisms for the induction of VTE remain to be fully elucidated, but it is widely acknowledged that tissue ...factor (TF)-bearing microparticles (TF-MPs) may play a significant role. However, TF-MPs have yet to be accepted as a genuine biomarker for cancer-associated VTE, as the presence of elevated TF-MP levels is not always accompanied by thrombosis; interestingly, in certain cases, particularly in pancreatic cancer, VTE seems to be more likely in the context of acute inflammation. Although several potential mechanisms for the development of VTE in cancer have been postulated, this review explores the homeostatic disruption of TF-MPs, as the main reservoir of bloodborne TF, in the context of cancer and inflammation, and considers the abrogated responses of the activated endothelium and mononuclear phagocyte system in mediating this disruption.
•Cancer-associated thrombosis is a major health problem that affects morbidity and mortality of people with cancer.•Surgical and systemic pharmacological anticancer treatments have a significant ...impact on the thrombotic risk of patients.•Primary thromboprophylaxis may be considered in high-risk ambulatory cancer patients using validated risk models.•Anticoagulant treatment of VTE in cancer patients is effective but may be associated with increased bleeding.•LMWH or DOACs are effective treatments and generally safe options for cancer-associated thrombosis.
In stage III colon cancer, oxaliplatin/5-fluorouracil (5-FU)-based adjuvant chemotherapy (FOLFOX) improves disease-free survival (DFS) and overall survival (OS). In rectal adenocarcinoma following ...neoadjuvant chemoradiation (CRT), we examined the benefit of postoperative adjuvant capecitabine and oxaliplatin (XELOX) chemotherapy.
Eligible patients were randomly assigned following fluoropyrimidine-based CRT and curative resection to observation or six cycles of XELOX. The primary end point was DFS; secondary end points were acute toxicity and OS. 390 patients were required in each arm, to detect an improvement in 3-year DFS from 40% to 50.5%, with 85% power and two-sided 5% significance level.
The study closed prematurely in 2008 because of poor accrual. Only 113 patients were randomly assigned to either observation (n = 59) or XELOX (n = 54). Compliance was poor, 93% allocated chemotherapy started and 48% completed six cycles. Protocolised dose reductions in XELOX were 39%, and levels of G3/G4 toxicity 40%. After a median follow-up of 44.8 months, 16 patients (27%) in the observation arm had relapsed or died compared with 12 patients (22%) in XELOX. The 3-year DFS rate was 78% with XELOX and 71% with observation hazard ratio (HR) for DFS = 0.80; 95% confidence interval (CI) 0.38–1.69; P = 0.56. The 3-year OS for XELOX and observation were 89% and 88%, respectively (HR for OS = 1.18; 95% CI 0.43–3.26; P = 0.75).
The observed improvement in DFS for adjuvant XELOX and similar OS were not statistically significant, as expected given the small number of patients and consequent low power. Our findings support the need for trials that test the role of neoadjuvant chemotherapy.
NCT00427713.
Abstract Background Annualised figures show an up to 7-fold higher incidence of vascular thromboembolism (VTE) in patients with advanced pancreatic cancer (APC) compared to other common malignancies. ...Concurrent VTE has been shown to confer a worse overall prognosis in APC. Methods One hundred and twenty three APC patients were randomised to receive either gemcitabine 1000 mg/m2 or the same with weight-adjusted dalteparin (WAD) for 12 weeks. Primary end-point was the reduction of all-type VTE during the study period. NCT00462852 , ISRCTN: 76464767. Findings The incidence of all-type VTE during the WAD treatment period (<100 days from randomisation) was reduced from 23% to 3.4% ( p = 0.002), with a risk ratio (RR)of 0.145, 95% confidence interval (CI) (0.035–0.612) and an 85% risk reduction. All-type VTE throughout the whole follow-up period was reduced from 28% to 12% ( p = 0.039), RR = 0.419, 95% CI (0.187–0.935) and a 58% risk reduction. Lethal VTE <100 days was seen only in the control arm, 8.3% compared to 0% ( p = 0.057), RR = 0.092, 95% CI (0.005–1.635). Interpretation Weight adjusted dalteparin used as primary prophylaxis for 12 weeks is safe and produces a highly significant reduction of all-type VTE during the prophylaxis period. The benefit is maintained after dalteparin withdrawal although decreases with time.
We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard ...chemotherapy.
Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression.
In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively).
Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.
ESSENTIALS: We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major ...hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE.
Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management.
Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed.
In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval CI 3.7-8.3%), 4.7% (95% CI 3.0-6.8%), and 37% (95% CI 28-47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio HR 0.9; 95% CI 0.3-3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91-7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6-10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50-2.4).
These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.
In this study the uptake of tissue factor (TF)-positive microparticles by endothelial cells and the recycling of the TF component were examined. Human dermal blood endothelial cells (HDBEC) were ...incubated with microparticles derived from cancer cell lines for up to 6 hours. Measurement of HDBEC cell surface TF antigen revealed two distinct peaks at 30 and 180-240 minutes post-incubation with TF-positive, but not TF-deficient microparticles. However, only the second peak was concurrent with high TF activity as determined by a chromogenic thrombin-generation assay. Annexin V-labelling of HDBEC showed phosphatidylserine exposure following 90 minutes incubation with microparticles, which explains the high TF activity associated with the second antigen peak. Analysis of TF mRNA levels revealed no de novo expression of TF mRNA in response to microparticles, and pre-incubation of cells with cycloheximide did not prevent the appearance of TF. However, blocking endocytosis with a dynamin inhibitor prolonged the disappearance and prevented the reappearance of TF antigen on the cell surface. Incubation of HDBEC with microparticles containing TF-GFP revealed the early co-localisation of TF with Rab4 and Rab5, followed by co-localisation with the late endosomal/trans-Golgi network marker Rab9, and the recycling endosome marker Rab11. siRNA-mediated suppression of Rab11 reduced the reappearance of TF on the cell surface. These data suggest a mechanism by which TF-containing microparticles are internalised by endothelial cells and the TF moiety recycled to the cell surface. Together with the exposure of phosphatidylserine, this is capable of inducing a substantial increase in the procoagulant potential of the surface of endothelial cells.
After more than 150 years of a recognised link between cancer and vascular thromboembolic events (VTE), and despite a greatly improved understanding of its pathophysiology, epidemiology and ...treatment, the management of patients with cancer and VTE is still limited. Limitations can be related to the thromboembolism itself, the underlying cancer, or to the management process. There is significant literature that deals with the first two, but very little regarding the systems we use, or how the inadequacies in documentation, identification and classification of VTE affect the cancer patients themselves. This review aims to raise awareness of this neglected area and stimulate research that may lead to improvements in patient care.
Introduction The calibrated automated thrombography (CAT) assay is emerging as a reliable tool for real time estimation of thrombin generation (TG) potential. As a time-dependent colorimetric ...assessment of thrombin quantity generated per sample, it measures the amount of thrombin-cleaved fluorogenic substrate produced, and so is regarded as a better overall indicator of the clotting efficiency and function of the haemostatic process than one stage clotting-time based assays. Aim We already recognise that the pathways underlying the thrombotic phenotype for different malignancies may be driven by different factors of the coagulation cascade with TG has a common denominator. Two such malignancies with high venous thromboembolism (VTE) incidence are Multiple myeloma (MM) and Pancreatic cancer (PC). Understanding the underlying variations in these two distinct cancer models using patient samples and cell lines might potentially allow individual approaches to identifying thrombotic risk and relevant prevention strategies. Materials and Methods Citrated blood samples were taken from healthy controls, pre-surgical pancreatic cancer and pre-chemotherapy multiple myeloma patients enrolled into ongoing clinical trials. The clotting ability was tested using platelet free plasma (PPP) on a one-step clotting time-based (CT) assay and the TG profiles were evaluated on a Thrombinoscope™ software (Thrombinoscope BV, Maastricht, Netherlands). Solid tumour cells of pancreatic cancer and malignant haematological cell lines were used at various cell concentrations for the CAT assay, which was performed with the addition of platelet-free control plasma or control plasma deficient in coagulation factors VII and XII. Results At TF concentration conditions of 1 pmol/L, the peak height of thrombin generated on thrombogram curves strongly correlated with CT of patient samples. Compared to healthy controls, pancreatic cancer had higher thrombin peaks (P), shorter lag times (LG), and an overall stronger TG profile than MM. Pancreatic cancer cell lines exhibited higher concentration-dependent TG profiles in control plasma than haematological cell lines, with higher peaks, endogenous thrombin potential (ETP), shorter lag times (LG) and faster times-to-peak (ttPeak). Conclusions This study demonstrates that the CAT assay is a useful predictor of the thrombotic phenotype in cancer patients as it gives a more comprehensive overall coagulation profile than one stage CT-based assays. It shows that for patient samples and cell lines, the similarities and differences that exists in the TG potential, significantly depends on specific coagulation factors present in the intrinsic or extrinsic arms of the clotting cascade.
Introduction The efficacy and safety of primary prophylaxis in advanced pancreatic cancer (APC) has been demonstrated in randomized controlled studies. Current guidelines suggest use of primary ...prophylaxis in high risk ambulatory cancer patients. The VTE in cancer working group in our centre reviewed our experience with FRAGEM and relevant literature. Observations: (1) Dose: (a) conventional prophylactic dosing is not established in APC (b) 200 IU/kg followed by 150 IU/kg dalteparin may be superior to 1 mg/kg followed by 40 mg enoxaparin. (2) Duration of treatment: (a) FRAGEM observed a rapid increase in VTE events after the 3-month treatment period. Transfer to 40 mg enoxaparin in CONKO-04 after 3 months also demonstrated reduced efficacy. (3) Recognition that bleeding in metastatic incurable pancreatic cancer is not uncommon even without anticoagulation. Cumulative incidence rates of major bleeding over the first 3 months were: 4.5% vs. 3.4% (NS) in CONKO-04 and 3.4% vs. 3.1 % (NS) in FRAGEM (treatment vs observation arms respectively). Aim This abstract describes our interpretation and experience on implementing available evidence for primary prophylaxis in ambulatory APC patients. Materials and Methods A simplified body weight-adjusted schedule for thromboprophylaxis with Dalteparin for the ambulant APC patient was agreed as follows: < 50 kg: 7500 IU, 50 - 80 kg: 10,000 IU, > 80 kg: 12,500 IU. Eligible patients: All patients with advanced / metastatic pancreatic cancer undergoing palliative chemotherapy. Dalteparin treatment was initiated at least one day prior to the first administration of chemotherapy and continued until death or unacceptable toxicity (bleeding). This guideline was implemented in May 2009. A departmental audit was conducted for patients treated till December 2012 to assess efficacy and safety. Results Results of the audit have been presented in an analysis including 67 patients. The compound adverse outcome (CAE) in this cohort was 24% (VTE: 13%, bleeding: 11%). For patients with no prior exposure to anticoagulation CAE rate was 18% (VTE: 7%, bleeding: 11%) with a median duration of LMWH treatment of 8 months. The majority of the bleeding events observed were due to cancer related lesions (duodenal infiltration or varices). VTE and bleeding rates were similar to published experience with extended duration therapeutic LMWH in cancer-related VTE. VTE risk appeared improved compared to the 3-month regimen of FRAGEM. Conclusions In our opinion, thromboprophylaxis in ambulatory APC is a pragmatic evidence-based approach trying to deal with a serious cancer related complication that affects these patients. It is expected that data from further randomised trials (e.g SELECT-D and CASSINI) will provide further evidence in this area.
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