Prophylaxis of VTE in the colorectal cancer patient

Colorectal cancer (CRC) is the third most common cancer worldwide and the most prevalent tumor in Western countries, affecting both genders. It accounts for approximately 10% of all cancer cases globally and is currently the second leading cause of cancer-related deaths worldwide, posing a significant concern for health authorities and providers [1] [2].

During the webinar “Management of CAT in colorectal cancer patients,” Dr. Andres J. Muñoz Martín delivered a lecture focused on the prophylaxis of VTE in colorectal cancer patients. Here, we provide a summary of the main points from his speech. You can also watch Andres J. Muñoz Martín’s lecture in the video below and the full webinar recording here. 

Risk Factors and Predictors of VTE in CRC Patients

Datasets from the RIETE registry, TESEO registry, and PREDICT-AI study show consistent findings: Apart from pancreatic cancer, CRC is the cancer most associated with VTE in terms of the number of patients [3] [4] [5] [6].

Dr. Muñoz reported that the Khorana score initially classified CRC as a low-risk tumor for VTE, but a new risk assessment model based on artificial intelligence has reclassified CRC as an intermediate-risk cancer for VTE [7].

He also stated that “nowadays, the complexity of VTE risk assessment in CRC patients is ever increasing, with more and more risk factors being considered, yet without a specific risk assessment model to predict the VTE risk.”

Regarding the link between CRC molecular profile and the risk of VTE, there are some conflicting results about biomarkers, particularly concerning K-RAS. Clinically, K-RAS appears to be a risk factor for VTE, but a meta-analysis does not support this hypothesis [8] [9].

Interestingly, as suggested by a study conducted by Dr. Muñoz, the B-RAF mutation could represent a strong VTE risk factor, as an incidence of VTE in B-RAF mutated CRC patients of around 29% was reported, compared to 20% in wild-type CRC patients [6]. Other studies have also confirmed this claim, and some authors have suggested that including the molecular profile and biomarkers such as B-RAF in VTE risk assessment models could improve their performance [10][11].

CRC treatment approaches and risk of VTE

The administration of chemotherapeutic agents commonly employed in CRC therapy, such as oxaliplatin, 5-fluorouracil (5FU), and irinotecan, is linked to a significant risk of VTE, which becomes 30% higher with anti-EGFR therapy involving monoclonal antibodies like cetuximab and panitumumab [12]. The application of amivantamab and necitumumab in non-small cell lung cancer is also associated with a high VTE risk [13].

Regarding bevacizumab, it is still unclear whether its use represents a protective factor or a risk factor for VTE, but it is certainly associated with a high risk of bleeding, a factor that must considered in prophylaxis management [14].

Other antiangiogenic therapies approved for CRC, such as aflibercept and ramucirumab, seem to have a better vascular toxicity profile, with a slightly lower risk of VTE. Therefore, it is necessary to consider the different drugs used in CRC patient management when developing a VTE risk assessment model or assessing the risk of bleeding and VTE [12].

Thromboprophylaxis Strategies in CRC: Surgical and Ambulatory Approaches

Patients undergoing colectomy who develop a VTE event have a risk of mortality that is approximately four times higher, making it a significant risk factor for overall mortality [15].

Furthermore, a randomized clinical trial demonstrated that laparoscopic surgery, which is commonly used in CRC, is associated with a high risk of VTE, and the extension of thromboprophylaxis with LMWH significantly reduces VTE events without increasing bleeding or mortality [16]. This finding is further supported by a meta-analysis that evaluated the use of LMWH in thromboprophylaxis over the past 30 years [17].

In addition, the Prolapse II trial indicated that extending thromboprophylaxis with the oral anticoagulant rivaroxaban following a short initial period of LMWH (7-10 days) is both effective and safe [18].

For the first time, the latest ASCO guidelines update reported rivaroxaban, along with apixaban, as valid alternative treatments for extended thromboprophylaxis in surgical cancer patients [19].

Notably, 30% of surgical patients who stop thromboprophylaxis develop a VTE event within 4 weeks. Therefore, a better risk assessment model is needed to identify these patients who may require an extension of thromboprophylaxis [20].

Regarding the ambulatory thromboprophylaxis setting, Dr. Munoz stated, “CRC patients face a significant risk of VTE, with incidence rates around 20% in patients with stage four disease. Despite evidence from numerous randomized clinical trials and meta-analyses supporting the use of LMWH and DOACs for thromboprophylaxis, utilization remains low among oncologists, with less than 5% of patients receiving it. This underutilization is due to several factors, including the lack of FDA approval, difficulties in identifying high-risk patients, and the heterogeneity of trial populations. Furthermore, there are no dedicated trials for CRC patients, unlike other cancers such as pancreatic cancer. The need for personalized medicine and targeted therapies is critical, with better biomarkers required to improve risk assessment. Recent data published in JAMA Oncology suggest that patient selection using D-dimer and other biomarkers may impact overall survival, emphasizing the need for further research and better implementation strategies”. 

The PRoTINCOL Study: An Independent Investigator-Initiated Trial

Dr. Munoz concluded his presentation by providing updates on the PRoTINCOL clinical trial (NCT05625932) currently in the recruitment phase, with no results published yet, and expected to conclude in 2025.

The PRoTINCOL study, launched last year in Spain, is an ongoing investigator trial by the Grupo Gallego de Investigación de Tumores Digestivos. This phase three randomized clinical trial focuses exclusively on metastatic CRC patients, with the aim to randomize 526 patients to receive either Tinzaparin or to follow a ‘watch and wait’ approach for four months.

Patients are randomized based on three key factors: whether their primary tumor has been resected, specific biomarkers (N-RAS, B-RAF, K-RAS mutations vs. wild type), and antiangiogenic therapy. This stratification is crucial as it considers the higher bleeding risk in non-resected tumors, and for the first time, a quality-of-life analysis is being performed using the EORTC QLQ-C30 questionnaire.

The primary endpoint of the study is the incidence of VTE, with multiple secondary endpoints, including genomic testing. The study will also evaluate various risk assessment scores, such as the Khorana score, CAT score, PROTECHT score, CONKO score, and LEE score. Despite not using any specific score for patient selection, the study considers stage four CRC as having a high risk for thromboprophylaxis.

Currently, the trial is actively recruiting, with 133 patients enrolled so far. The first internal analysis of 111 patients showed promising progress. The study will also investigate the effects of discontinuing thromboprophylaxis after four months to determine if there is a rebound effect or if the intervention provides true prevention.

The PRoTINCOL trial is considered a unique clinical trial due to its homogeneous population, focusing solely on stage four CRC. It aims to incorporate personalized medicine, using both patient and cancer genomics to build a new risk assessment model. The trial will dynamically assess various biomarkers, such as D-dimer, and involve 23 centers in Spain, with plans to expand to Portugal.

The study’s comprehensive approach, including quality of life assessment and the evaluation of different treatment profiles, aims to provide valuable data on the management of CRC patients and their risk of VTE. The findings could significantly impact future strategies for thromboprophylaxis in this patient population.

Conclusion

The risk of VTE in CRC patients is a significant concern, with multiple studies highlighting the heightened incidence associated with specific treatments and genetic profiles. Current research underscores the complexity of VTE risk assessment in CRC, particularly with the influence of molecular biomarkers such as B-RAF and K-RAS.

The innovative PRoTINCOL study aims to address these gaps by focusing on personalized medicine and comprehensive risk assessment strategies. Advancing our understanding of VTE risk factors and improving prophylactic measures can lead to better clinical outcomes for CRC patients, emphasizing the need for continued research and implementation of tailored thromboprophylaxis strategies.

Watch Muñoz’s lecture:

References

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