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Essentials Competing risk by death may lead to overestimation of venous thromboembolism (VTE) risk in cancers. We assessed the risk of VTE in cancer with and without accounting for competing risk by death. The risk of VTE was influenced by the mortality rate and the time since cancer diagnosis. Competing risk by death should be taken into account when exploring VTE risk in cancer. Summary: Background Venous thromboembolism (VTE) is a common complication in cancer, and studies have suggested that aggressive cancers create the highest risk of VTE. However, competing risk by death may result in overestimation of VTE risk in patients with cancers associated with high mortality. Therefore, we estimated the risk of VTE by cancer site, accounting for the differential mortality between cancers. Methods The Scandinavian Thrombosis and Cancer cohort included 144 952 participants followed from 1993–1997 to 2008–2012. Incidence rates, cause-specific hazard ratios (HRs) and subdistribution HRs (SHRs) were assessed for overall cancer and by cancer site according to time intervals since cancer diagnosis. Results During follow-up, 14 272 subjects developed cancer, and 567 had cancer-related VTE. In cause-specific analyses, the VTE risk was highest in the first 6 months after cancer diagnosis (HR 17.5, 95% confidence interval [CI] 15.1–20.3), and declined rapidly thereafter. However, when mortality was taken into account, the risk was similar in the periods 6 months before (SHR 4.8, 95% CI 3.6–6.4) and 6 months after (SHR 4.6, 95% CI 3.9–5.4) cancer diagnosis. The range of the 2-year cumulative VTE incidence rates was substantially narrowed for all cancer sites after competing risk by death was taken into account (from 1–10% to 1–4%). Conclusion VTE risk by cancer site was influenced by the mortality rate and the time since cancer diagnosis. Our findings suggest that the cancer itself is a major contributor to VTE risk, and that competing risk by death should be taken into account when VTE risk in cancer is explored.

Source: doi: 10.3324/haematol.2016.147405 Venous thromboembolism occurs frequently in cancer patients. Two variants in the factor 5 gene (F5), rs6025 encoding for the factor V Leiden mutation R506Q, and rs4524 encoding K858R, have been found to be associated with venous thromboembolism. We assessed the joint effect of active cancer and these two F5 variants on venous thromboembolism risk in a case-cohort study. Cases with a first venous thromboembolism (n=609) and a randomly selected age-weighted cohort (n=1,691) were sampled from the general population in Tromsø, Norway. Venous thromboembolism was classified as cancer-related if it occurred in the period 6 months before to 2 years after a diagnosis of cancer. Active cancer was associated with an 8.9-fold higher risk of venous thromboembolism (95% CI 7.2–10.9). The risk of cancer-related venous thromboembolism was 16.7-fold (95% CI 9.9–28.0) higher in subjects heterozygous for rs6025 compared with non-carriers of this variant without active cancer. In subjects with active cancer the risk of venous thromboembolism was 15.9-fold higher (95% CI 9.1–27.9) in those with one risk allele at rs4524, and 21.1-fold (95% CI 12.4–35.8) higher in those with two risk alleles compared with non-carriers without active cancer. A synergistic interaction was observed between active cancer and factor V Leiden (relative excess risk due to interaction 7.0; 95% CI 0.5–14.4) and rs4524 (relative excess risk due to interaction 15.0; 95% CI 7.5–29.2). The incidence of venous thromboembolism during the initial 6 months following a diagnosis of cancer was particularly high in subjects with risk alleles at these loci. This implies that the combination of cancer and F5 variants synergistically increases venous thromboembolism risk.

Background Although venous thromboembolism (VTE) is a known common complication in cancer patients, there is limited knowledge on patient-related and cancer-specific risk factors in the general population. The Scandinavian Thrombosis and Cancer (STAC) Cohort was established by merging individual data from three large Scandinavian cohorts (The Tromsø Study, the second Nord-Trøndelag Health Study, and the Danish Diet, Cancer and Health Study). Here, we present the profile of the STAC cohort and provide age-specific incidence rates of VTE and cancer. Methods The STAC cohort includes 144,952 subjects aged 19–101 years without previous VTE or cancer. Baseline information collected in 1993–1997 included physical examination, self-administered questionnaires, and blood samples. Validated VTE events and cancer diagnoses were registered up to 2007–2012. Results There were 2,444 VTE events (1.4 per 1,000 person-years [PY]) during follow-up, and the incidence increased exponentially from 0.3 per 1,000 PY in subjects aged 20–29 years to 6.4 per 1,000 PY in subjects aged 80+. Overall, 51% of the VTE events were provoked, and cancer was the most common provoking factor (19%), followed by immobilization and surgery (both 15%). In total, 19,757 subjects developed cancer during follow-up (9.8 per 1,000 PY), and the 5-year age-specific incidence rates of cancer were coherent with corresponding rates from the Norwegian Cancer Registry. Conclusion The STAC cohort will provide a unique opportunity to explore the epidemiology and impact of genetic and environmental patient-related and cancer-specific risk factors for VTE in the general population.

[Graphic][1] Background: Several studies have shown a high incidence of venous thromboembolism (VTE) in hematological cancers, comparable with solid cancers, although bleeding is also a prominent complication of the hematological patients. Cancer patients, who develop VTE, have a reduced survival and impaired quality of life if compared to those who do not develop VTE. Hematological cancers are rather rare diseases and most studies have described only some of the entities. Here we want to compare the incidence of VTE in seven subtypes in a large cohort. Aim: To investigate the risk of VTE in hematological malignancies compared to matched controls in a prospective population based cohort study, the Scandinavian Thrombosis and Cancer (STAC) Cohort. Methods: TheSTAC Cohort includes 144.952 participants from three population based prospective cohort studies, i.e. The Tromso Study and the HUNT2 study from Norway, and the Danish Diet, Cancer and Health Study. The participants were enrolled during 1993-1997, and mean follow-up time was 11.7 years. The cohort profile and outcome of first time objectively confirmed VTE events have been described in prior studies. For this study we collected data from the national cancer registries using morphology codes to identify cohort subjects with hematological cancers, divided into 7 groups: multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute leukemia (myeloid and lymphoblastic) (AL), chronic myeloproliferative neoplasms and myelodysplastic syndrome (CMN/MDS), aggressive non-Hodgkin lymphoma (aggr. NHL), Hodgkin lymphoma (HL), and indolent lymphoma (Ind. L). Subjects with a VTE event more than one year before cancer diagnosis were excluded. For each of the cases 5 controls matched on country, sex and age were identified. We used Cox regression models to estimate the relative risk of VTE across the seven different subtypes of hematological malignancies with a time axis starting one year before the diagnosis of cancer (and similar for matched controls) and ending at a VTE event or end of follow-up. Data were adjusted for age by spline regression. Results: During follow-up 891 participants were diagnosed with a hematological malignancy, and in this group 41 VTE events were observed corresponding to an incidence of 12.0 events per 1000 person-years (10-3 p-y). In the control group of 4455 participants 55 VTE events were observed which gave an incidence of events on 2.3* 10-3 p-y. Having a hematological cancer including all seven investigated types was associated with a six-fold increased risk of developing VTE compared to the matched controls. During follow-up 203 participants were diagnosed with MM, and 10 VTE events were observed giving an event rate of 14.6*10-3 p-y; hazard ratio (HR) for VTE was 7.2, 95% confidence interval (CI): 3.6-14.3. CLL was diagnosed in 176 cases, and 11 VTE events were observed in this group (event rate 11.5*10-3 p-y; HR 5.3; 95% CI: 2.7-10.1). Among the 63 participants who were diagnosed with AL during follow-up 2 VTE events were observed corresponding to an event-rate on 12.8*10-3 p-y; (HR 6.9; 95% CI: 1.7-29.0). In the group of CMN/MDS 4 VTE events were observed among 104 patients (event-rate 12.0*10-3 p-y; HR 6.4, 95% CI: 2.3-18.0). In aggressive NHL 10 VTE events were observed among 158 patients resulting in an event-rate of 18.9*10-3 p-y (HR 10.4; 95% CI: 5.2-20.8). Forty-four participants were diagnosed with HL, and 2 VTE events were observed which corresponds to an event-rate of 10.6*10-3 p-y among these patients (HR 5.1; 95% CI: 1.2-21.4). Indolent lymphoma was diagnosed in 143 subjects, and 2 VTE events were observed (event-rate 3.5*10-3 p-y; HR 1.9; 95% CI: 0.47-8.0). The results are summarized in the table: | | MM | CLL | AL | CMN/MDS | Aggr. NHL | HL | Ind. L | | --------------------- | -------- | -------- | -------- | -------- | --------- | -------- | -------- | | N | 203 | 176 | 63 | 104 | 158 | 44 | 143 | | VTE (n) | 10 | 11 | 2 | 4 | 10 | 2 | 2 | | Incidence (*10-3 p-y) | 14.6 | 11.5 | 12.8 | 12.0 | 18.9 | 10.6 | 3.5 | | HR | 7.2 | 5.3 | 6.9 | 6.4 | 10.4 | 5.1 | 1.9 | | 95 % CI | 3.6-14.3 | 2.7-10.1 | 1.7-29.0 | 2.3-18.0 | 5.2-20.8 | 1.2-21.4 | 0.47-8.0 | Table. Conclusion: Indolent lymphoma was the only investigated hematological malignancy that was not associated with a significant increased risk of VTE. The other types of hematological malignancies had an increased risk of VTE ranging from approximately 5-10 times, highest in aggressive non-Hodgkin lymphoma and lowest in Hodgkin lymphoma. However a limitation of the study is the small numbers in some of the groups in spite of the large cohort. Disclosures No relevant conflicts of interest to declare. [1]: /embed/inline-graphic-2.gif

Background: Leukocytosis is an independent risk factor for mortality in cancer patients. Elevated white blood cell (WBC) count, and neutrophils in particular, is also associated with increased risk of venous thromboembolism (VTE) in patients with manifest cancer initiating chemotherapy. It is not known whether the risk of VTE by WBC in cancer patients is causal or merely a consequence of the disease. To address this question we studied the association between WBC count, measured prior to cancer development, and risk of VTE in subjects without and with development of cancer during follow-up in a prospective population-based study. Methods: Baseline characteristics, including total WBC and neutrophil counts, were measured in 24463 initially cancer-free subjects who participated in the Tromso study in 1994–1995. Cancer diagnosed at least one year after WBC measurements and incident venous thromboembolism occurring after the cancer diagnoses were registered up to September 1st, 2007. Cox-regression models were used to calculate hazard ratios (HR) with 95% confidence interval (CI) for VTE. Results: There were 1647 subjects who developed cancer and 353 incident VTE events, ofwhich 84 (24%) occurred in the cancer-group (15.6 per 1000 person-years) and 269 (76%) in the cancer-free group (1.15 per 1000person-years) during follow-up. The risk of VTE increased by 29%per one standard deviation (1SD=2.38×109 cells/L) increase in total WBC (multivariable HR 1.29; 95% CI 1.14–1.46) among cancer patients. WBC count≥8.5×109 cells/L was associated with a 2-fold higher adjusted risk of VTE compared to WBC countb6.5×109 cells/L (HR 2.0, 95% CI 1.163.72). Similar findings were observed for neutrophils. No association was found betweenWBC count and VTE in cancer-free subjects. Comment: Total WBC and neutrophil counts measured prior to cancer development were associated with risk of VTE in cancer patients, but not in cancer-free subjects. Our findings suggest that neutrophils may play a causative role inVTE among cancer patients rather thanonly reflecting the low-grade inflammation associated with cancer.