Introduction

Venous thromboembolism (VTE) is defined broadly to include deep venous thrombosis (DVT), pulmonary embolism (PE), superficial vein thrombosis (SVT) and thrombosis in the other vascular territories. The association between VTE and malignancy was first reported by Armand Trousseau in 1865 and is supported by the results of more studies [1, 2]. In a population-based study, cancer was associated with a 4.1-fold greater risk of thrombosis, whereas the use of chemotherapy increased the risk 6.5-fold [3]. Virchow’s triad of stasis, thrombophilia, and endothelial injury plays a critical role in the pathophysiology of VTE in patients with cancer. However, a second triad comprising changes in tumor biology, coagulation activation, and inflammation further describes the pathogenesis of thrombosis in the patient with malignancy [4].

It is unclear from available studies whether the risk of VTE is increasing for all cancers or only for specific subgroups of cancer patients. We hypothesized that the rate of VTE was increasing primarily in patients on active chemotherapy and was not because of increased diagnostic testing. Cancer sites, such as the pancreas, stomach, brain, lung, and metastatic disease are associated with higher rates of VTE in multiple studies [5–7].

The incidence of VTE in cancer patients has been difficult to determine due to the heterogeneity of the patient population [8]. Thus, identifying clinical characteristics that predispose cancer patients to increased risk of VTE is important to achieve better outcomes. There is limited data about VTE in cancer in Saudi Arabia; we undertook this study to evaluate the frequency, clinical pattern and outcome.

The primary end point of the current retrospective study was to evaluate the prevalence of VTE in cancer patients and the correlation with the demographic features, secondary end point was to evaluate the overall survival; in King Abdullah Medical City; a Saudi tertiary care hospital.

Materials and Methods

In our retrospective study, we reviewed medical records of cancer patients in King Abdullah Medical City—Holy Capital. We targeted patients during the period from May 2011 to June 2013.

The eligibility criteria were; age ≥18 years, pathological diagnosis of cancer, and objectively proven VTE. History of a thromboembolic event was determined on the basis of information in the patients’ records at the primary medical evaluation and follow-up clinic visits. The following data were collected; the demographic features including (sex, age, marital status and residence), disease stage, timing of VTE in relation to cancer diagnosis either before or simultaneous or after it. The diagnosis of thromboembolic event was based on the clinical back ground; the presentation and by imaging studies; Doppler ultrasound, computed tomography and angiography.

Follow up period was calculated from time of VTE diagnosis till the last clinical visit at the time of data collection or till the death of patients.

Statistical Analysis

Data collected were analyzed using SPSS computer soft ware. Continuous variables were summarized using mean, median, mode and standard deviation. Chi square test was used for categorical variables. Student’s t test was used t-test for numerical data. Significance was defined as a p value of <0.05. Multivariate logistic regression analysis was used to determine predictor variables that are associated with outcome.

Results

Patient Characteristics

We reviewed the medical record of 1,678 cancer patients (solid and hematology tumors) treated in KAMC oncology center during the study period. Demographic characteristics are summarized in Table 1.

Table 1 Patient characteristics
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The median age at the time of diagnosis was 53.5 years (range, 15–84 years), with female to male ratio of patients 1.3/1.

The VTE was categorized as symptomatic in 110 patients (83.3 %), and asymptomatic (discovered accidently during routine radiological investigations and/or clinical judgment as documented in the files) in 22 patients (16.7 %).

There were 31 patients (23.5 %) with concurrently diagnosed VTE, 74 patients (56.1 %) during chemotherapy and 28 patients (21.2 %) during the best supportive care period (No treatment modifying agents).

Off all VTE cases, only 37 % patients received prophylactic dose of low molecular weight heparin (LMWH), with 11 patients developed treatment related complications (six patients developed bleeding and five patients developed thrombocytopenia), where they managed by putting IVC filter.

Among the patients receiving chemotherapy, 4.41 % developed VTE which is greater than the rate observed in the rest of study group (3.5 %).

The basic features of asymptomatic VTE are summarized in Table 2.

Table 2 Features of Asymptomatic VTE
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Venous Thromboembolism

Among 1,678 cancer cases were treated during the study period, VTE was diagnosed in 7.87 %. The most common type of VTE was DVT in the lower limbs in 56 patients (42.4 %), followed by DVT in upper limbs in 32 patients (24.4 %), and PE in 16 patients (12.1 %). More details are shown in Table 3.

Table 3 Type of thrombosis
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Distribution of Underlying Malignancy Associated with VTE

The most common type of cancers associated with thrombosis were non-Hodgkin’s lymphoma, colon, acute leukemia, genitourinary and breast cancer. Majority of the patients (93 %) with VTE diagnosis had advanced stage of cancer. The type and stage of cancer are given in Table 4.

Table 4 Distribution of underlying malignancy associated with VTE
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Survival Analysis

Log rank (Mantel-Cox) survival analysis was summarized in Table 5.

Table 5 Survival groups
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Figure 1, shows the survival curve for patients with symptomatic and asymptomatic.

Fig. 1
figure 1

Log rank (Mantel-Cox) survival analysis showed no difference in overall survival was found between symptomatic and asymptomatic patients (p = 0.88)

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VTE (median survival 12.4 months vs 9.8 months, respectively; p = 0.88 with no significant difference). Also there is no difference in overall survival between patients with VTE prophylaxis versus no prophylaxis group (median survival 12.6 months vs 6.3 months, respectively; p = 0.12) as shown in Fig. 2.

Fig. 2
figure 2

Log rank (Mantel-Cox) survival analysis showed no difference in overall survival was found between patients who have been given prophylaxis versus no prophylaxis group (p = 0.12)

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Discussion

VTE represents one of the most important causes of morbidity and mortality in cancer patients. It has important implications on cancer patients; these include significantly worse survival, compromised quality of life, and increased the risk of bleeding complication following the use of anticoagulants, risk of recurrent VTE and additional burden on the resources [9].

To our knowledge, No population-based study has determined the incidence of VTE among patients diagnosed with specific types and stages of cancer. Reported rates of VTE in cancer patients range from as low as 1.6 % to as high as 20 % [10–13]. In addition to this real difference, variations in these estimates may also depend on the study design, case definition, and age distribution. The rate of VTE in our study was not very high (7.9 %). However, we believe that the actual rate is much higher than our results. This may be due to the retrospective nature of the study in addition to death of some patients from cancer before diagnosis of VTE. Third, autopsies for diagnostic purposes are usually not carried out routinely in Saudi Arabia because of religious and cultural beliefs, so it is reasonable to believe that the actual rate of VTE in Saudi cancer patients is probably much higher than found in our study.

In our study, VTE was diagnosed in 31 patients (23.5 %) simultaneously with cancer diagnosis and incidentally during routine investigation which are frequently reported in other studies; in a retrospective cohort analysis by Moore et al., 44 % of all VTE events were incidental diagnosed and in another cohort study by Singh et al., 50 % of DVTs and 35 % of PEs were incidentally discovered [14–19].

An important finding from our study is the presence of a considerable number of patients with asymptomatic thrombosis; 22 patients (16.7 %), and the majority of these patients had thrombosis in abdominal vessels; 13 patients (9.8 %) and four patients were found to have PE.

The high percentage of asymptomatic VTE raises the question of screening. There is much uncertainty about of which, if any, subgroups should be screened, and whether this would have an important impact on clinical outcome so, the routine screening for VTE in cancer patients till now is generally not recommended. In our center, we generally start by therapeutic dose anticoagulation for all cancer patients with asymptomatic VTE.

Another important finding from our study is the under utilization of thrombosis prophylaxis in cancer patients; only 49 patients (37.9 %) received medical prophylaxis. Several studies from around the world have consistently shown a lack of prophylaxis in hospitalized medical patients, including cancer patients [20, 21]. This is a particular problem in the developing countries but also a common observation even in the developed countries [22, 23]. There are several reasons that might explain why prophylaxis is not a widespread practice, include; failure to appreciate the risk of VTE in medical and cancer patients, complexity of existing risk assessment models, poor implementation and compliance with the guidelines, and cost issues.

Although VTE commonly occurs in patients with cancer, most oncologists underestimate both the prevalence of VTE and its negative impaction. With this background in mind, The American Society of Clinical Oncology (ASCO) first published an evidence-based clinical practice guideline on prophylaxis and treatment of VTE in 2007 [24], and updated at intervals determined by an Update Committee in 2013 [25].

Given the underutilization of VTE prophylaxis in cancer patients, an integrated risk stratification checklist along with a pre-printed order sheet for VTE prophylaxis is a useful way of promoting its use, and should be part of the routine assessment of all cancer patients.

The impact of symptomatic VTE on survival is described in literatures [26, 27]. Sorensen et al. found that the 1-year survival rate for cancer patients with thrombosis was 12 % compared with 36 % in control patients (p < 0.001) [28]. This high mortality was thought to reflect deaths due to both thromboembolism and a more aggressive course of malignancies associated with VTE. In our study; 1-year survival rate for cancer patients with thrombosis was 18.9 %. Survival analysis showed no difference in overall survival between patients with VTE prophylaxis versus no prophylaxis group (12.6 months vs 6.3 months, respectively) (p = 0.12), which did not match with literatures. This can be explained by the difference in sample sizes, type or stage of cancer in addition to the retrospective nature of the study.

Also there was no difference in overall survival between symptomatic and asymptomatic patients (12.4 months, 9.8 months respectively; p = 0.885). To our knowledge, no long-term survival studies of patients with an asymptomatic VTE have been reported in the literature. Engelke et al. in a retrospective study found that those with an incidentally diagnosed VTE, despite failure to treat, had a benign prognosis [29]. This retrospective trial was also limited by small patient numbers, and the investigators recommended further assessment.

Limitations

The potential limitations of this study included the fact that information about some patients was incomplete in view of the retrospective nature of the study might have introduced some bias in our findings. Specifically, there was not enough information about chemotherapy type, radiotherapy, hormone therapy or targeted therapy.

Small sample size is also one of the most limiting factor, owing to the given sample size, one further limitation of the study is the low number of events when separating according to sites (abdominal, superficial, distal, proximal) or presentation (symptomatic, asymptomatic) DVT for outcome analysis. Therefore, larger prospective studies are needed to validate our findings and which are powered to detect differences in short-term survival between the above-mentioned subgroups of venous thrombosis. Furthermore, we did not measure recently published blood-based biomarkers, such as tissue factor which may be helpful in management of asymptomatic DVT.

Conclusion

Although the incidence of VTE in our region is not very high; it may be underestimated due to multiple factors, added to underutilization of thromboprophylaxis. Regardless of the cause, VTE in cancer patients is of considerable consequence, given its strong association with poor survival. Much work needs to be done to reduce the burden of VTE among cancer patients.