An Overview of VTE Prevention and Management in Gynecological Cancer Care

As with cancers in general, gynecological cancers also exhibit a clear and increasingly significant association with venous thromboembolism (VTE), which, after cancer itself, is the second leading cause of death among cancer patients [1,2,3].

Current guidelines generally recommend pharmacologic prophylaxis for VTE with a careful and individualized preventive approach for hospitalized, surgical, and medical cancer patients and selected ambulatory patients [4]. The thrombogenic potential varies depending on the type of cancer, disease stage, or presence of certain oncogenic mutations [4]. Therefore, assessing VTE’s specific and individualized risk is crucial [5]. The development of cancer-specific risk assessment models (RAMs) aims to enhance risk stratification approaches, potentially integrating promising biomarkers [4].

The prevention and management of VTE in gynecological malignancies is particularly challenging due to the complex pathophysiology and the involvement of various factors, some of which are specific to gynecological tumors, that can influence the risk of VTE [6,7].

Despite this, literature data indicate an underestimation of VTE in the gynecological context, emphasizing the need to shed light on potential risk factors, RAMs, and pharmacological prophylaxis related to this type of malignancy [4].

Understanding VTE Risk in Gynecological Cancer

While age, diabetes, hypertension, and high body mass index have been shown to be significant VTE risk factors in the general cancer population, data on the relevance of the latter in gynecological cancer patients have been inconsistent [7,8]. The VTE risk profile in these patients is strictly related to specific gynecological tumor factors, such as type, size, and stage [4].

In particular, the ovarian cancer population, especially within the first year after diagnosis and among those with a histological diagnosis of clear-cell carcinoma [9,10], has been identified as being at the highest risk for VTE compared to cervical and endometrial cancer patients [4]. This elevated risk is likely since over 80% of ovarian cancer patients are diagnosed at a late stage, often with metastatic disease, a condition independently associated with an increased VTE risk [4,6]. Additionally, the location of the tumor in the pelvis often leads to massive ascites that compress the major blood vessels, along with various procoagulant factors released by the tumor [6].

Regarding cervical cancer, the risk of VTE is related to the presence of bulky lymph nodes in advanced stages, which increases the likelihood of lymphadenopathy-related pelvic vein compression, as well as the overall tumor size, with tumors larger than 50 mm linked to a nine-fold increase in the risk of VTE [4,8].

On the other hand, the incidence of VTE in endometrial cancer patients appears to be particularly influenced by factors such as hypertension, diabetes, obesity, and advanced age. Additionally, it depends on tumor histology, with endometrial grade 3 histology being associated with a higher likelihood of VTE incidence within 6 months compared to lower-grade histologies [11].

Importantly, the higher risk of VTE in ovarian and endometrial cancer subgroups may be attributed to the expression of tissue factors in these tumors [4], a key initiator of the coagulation cascade, whose activity can be mediated by various oncogenes [12].

The risk of VTE is also influenced by the status of the gynecological tumor, with active and recurrent cancers promoting prothrombotic states through tumor-related inflammation, the release of procoagulant factors, and the involvement of aggressive treatments [4,13]. Surgery and anticancer therapies, indeed, are associated with an increased risk of VTE. Reports indicate that, despite prophylaxis, VTE occurs in 6–7% of gynecologic cancer patients following surgery, with a 14-fold increased risk of pulmonary embolism (PE) compared to those undergoing surgery for benign conditions [14]. Meanwhile, the increased VTE risk linked to anticancer agents depends on their pharmacological properties, which may cause endothelial injury, reduce anticoagulant levels, or enhance procoagulant activity [15].

Risk Assessment for VTE in Gynecological Cancer

Generally, the stratification of patients for prophylactic therapy is crucial, and several RAMs have been developed to identify cancer patients at higher risk for VTE across various oncology settings. These include the Padua and Vienna-CATS prediction scores, the IMPROVE VTE RAM, the COMPASS-CAT model, the Caprini risk score, the ONKOTEV Risk Prediction Model, as well as the ONCOTHROMB  and Khorana scores [4].

However, in the studies that developed and validated these RAMs, gynecological cancer patients were underrepresented, comprising less than 10% of the total study population. Notably, the Khorana score has limited value for the gynecological cancer population, as it places these patients in the intermediate-risk category, thereby failing to accurately identify those at lower risk. This limited representation reduces the applicability of these models in the gynecologic oncology setting, highlighting the need for RAMs specifically designed for this patient group [4,6].

Some RAMs have been specifically developed to assess VTE risk in patients with gynecological malignancies, although none of these models have been externally validated [16,17]. Among them, Wang et al. initially developed a nomogram model, which showed high accuracy based on risk factors like age, D-dimer levels, body mass index, and surgical approach [18]. They later developed an additional nomogram specifically designed to predict VTE risk in patients with epithelial ovarian cancer, incorporating predictors such as progesterone receptor status and Ki-67 immunohistochemistry positivity [17]. Another example is the Thrombogyn score, tailored for gynecological cancer patients undergoing surgery and chemotherapy. This score includes variables like body mass index, chemotherapy treatment, and hemoglobin levels, along with the addition of procoagulant-based biomarkers, which improved its predictive power [16].

Pharmacological Strategies for VTE Prevention in Gynecological Cancer

In clinical practice, guidelines for VTE prevention in the general cancer population also apply to gynecological cancer patients, with variations based on whether patients are hospitalized, undergoing surgery, or receiving ambulatory care [4].

Hospitalized gynecological cancer patients have more than twice the risk of VTE compared to the general population [19]. Major guidelines recommend pharmacological prophylaxis with low-molecular-weight heparin (LMWH), unfractionated heparin, or fondaparinux (a factor Xa inhibitor) for all hospitalized cancer patients [5].

For patients undergoing major surgery, although the optimal duration of thromboprophylaxis remains unclear, guidelines suggest using unfractionated heparin or LMWH unless contraindicated due to a high bleeding risk. Prophylaxis is typically recommended for about 10 days but can be extended in selected patients depending on their VTE risk profile, potentially with the addition of direct oral anticoagulants (DOACs) [4]. Specifically for gynecological surgical cancer patients, studies have shown that combining sequential compression devices with LMWH provides the best balance between preventing VTE and minimizing the risk of major bleeding [20].

Additionally, cancer patients receiving systemic treatment are among those at the highest risk for thromboembolic complications due to the thrombogenic potential of treatments commonly used in this setting, such as 5-fluorouracil, capecitabine, gemcitabine, hormonal therapy, platinum compounds, and anti-angiogenesis treatments like bevacizumab. The latter two are particularly associated with a higher risk of VTE in gynecological cancer patients [4].

Furthermore, guidelines generally recommend medical prophylaxis for ambulatory outpatients undergoing systemic therapy if they are considered at high risk based on RAMs [4,5]. In patients with a Khorana score of ≥2, indicating intermediate to high VTE risk, prophylaxis with LMWH or DOACs has been shown to reduce VTE incidence without significantly increasing the risk of major bleeding [21].

However, some of the most recent guidelines do not routinely recommend medical prophylaxis in ambulatory gynecological cancer patients and instead suggest inserting central venous catheters on the right side and using a port rather than peripherally inserted central venous catheters to reduce VTE-related complications [22]. This recommendation is supported by advancements in insertion techniques and the use of less thrombogenic materials in modern catheters. In central venous catheter-related VTE cases, a three-month course of anticoagulant therapy with LMWH is preferred [4].

Conclusions

Current knowledge about the prevention and management of VTE in gynecological malignancies is largely derived from studies on solid cancers in general, which highlight a persistent heterogeneity in prophylactic protocols for VTE in clinical practice. In this context, further large and well-designed studies specifically focused on the management of VTE in gynecological cancer are urgently needed. At present, the best approach to VTE prevention and management involves integrating current guidelines with a multidisciplinary team approach [4].

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