Treatment of VTE in the colorectal cancer patient

In clinical practice, cancer-associated thrombosis (CAT) is a frequent phenomenon among colorectal cancer (CRC) patients. The presence of metastases, tumor invasion, and the use of anticancer treatments (i.e. chemotherapy, radiotherapy, surgery, anti-angiogenic agents), as well as the production of tumor-specific pro-thrombotic mediators lead to the onset of thrombosis. [1]

During the ICTHIC webinar titled “Management of CAT in colorectal cancer patients,” Dr. Alfonso De Stefano provided an overview of CAT risk factors and treatments in CRC patients. Here, we summarize the main points from his speech. You can watch Alfonso De Stefano’s lecture in the video below and the full webinar video here.

Colorectal cancer and CAT

Patients with cancer account for 20% of all cases of VTE, which is the second leading cause of death in cancer patients. [2] A study published in 2016 analyzed 4,000 patients, of whom 15% were affected by gastrointestinal (GI) tumors. The results showed that the presence of VTE significantly negatively influenced the overall survival. [3]

In a recent network meta-analysis reported by Dr. De Stefano, CAT was analyzed in relation to tumor type. CRC was found to be the ninth most common cancer associated with CAT. However, when considering factors such as chemotherapy, surgery, and advanced-stage disease, its ranking increases to the sixth or seventh place. [4]

Notably, 8% of CRC patients at the metastatic stage present VTE. [5] Other factors that may promote the onset of thrombosis include the presence of a central venous catheter, blood transfusion, and particularly the use of platinum-derived drugs (e.g., oxaliplatin) and 5-fluorouracil (5FU) or its prodrug, capecitabine, used in adjuvant or metastatic settings, which can increase the incidence of VTE up to 15%. This percentage can double if the use of corticosteroids prior to chemotherapy or erythropoietin-stimulating agents, often used in cases of anemia, is combined. [6-7]

CRC treatments and risks of VTE

Dr. De Stefano presented a forest plot detailing all the registration trials for Bevacizumab, a widely used anti-VEGF moAb in the treatment of CRC. In four of these trials, where Bevacizumab was used in conjunction with first-line chemotherapy, the administration of Bevacizumab was associated with the onset of thrombosis, with 19% of treated patients developing an all-grade VTE and 7% developing a high-grade VTE. [8]

On the other hand, the results of a recent publication suggest that bevacizumab has a protective effect in reducing the probability of developing VTE. The issue remains unclear, but De Stefano states that in his clinical practice, the use of anti-VEGF moAbs is considered a potential risk factor for the onset of thromboembolic events. [9]

Another anti-VEGF moAbs associated with vascular toxicity is aflibercept. Its use in a registration trial led to the onset of VTE in 9% of the enrolled patients. [10]

A further factor to consider is the presence of KRAS mutations. Dr. De Stefano recommends evaluating the presence of RAS and BRAF mutations before starting chemotherapy for first-line metastatic CRC patients. The presence of a KRAS mutation is a negative predictive factor for the use of anti-GFR (Growth Factor Receptors) therapies and is associated with a higher cumulative incidence of thromboembolic events. [11]

Oxaliplatin is the platinum-derived chemotherapeutic agent more used for patients in adjuvant settings, together with capecitabine or fluorouracil, or in a second-stage risk and metastatic setting. The maximum percentage of vascular toxicity reported in patients treated with oxaliplatin is 7%. [12]

In recent years, immunotherapies such as pembrolizumab, nivolumab, and the anti-CTLA-4 agent Ipilimumab have been indicated for the treatment of patients with microsatellite instability, including those with CRC. However, it is reported that thromboembolism has occurred in nearly one-third of all populations treated. [13]

Management of CAT

About 40% of CRC patients are elderly, characterized by numerous comorbidities, such as renal impairment or hypertension. [14]

Several factors influencing treatments include surgery, radiotherapy, and chemotherapy, which induce vomiting, diarrhea, and mucositis, thus limiting the oral absorption of drugs. In particular, patients with ileostomies are at a high risk of dehydration, which can exacerbate renal impairment and altered creatinine clearance, necessitating adjustments in the dosage of chemotherapy and all supportive care. Moreover, patients with liver metastases experience hepatic dysfunction, which alters the absorption of drugs. [15]

Therefore, Dr. De Stefano highlighted the recent ESMO guidelines suggesting various treatment options for both the initial and long-term phases of anticoagulant therapy and recommending the use of low molecular weight heparins (LMWH) when the in situ primary CRC tumor is present. [1]

It is crucial, in the setting of CRC patients, to emphasize the relevance of the persistence of in situ primary tumor, which poses a high risk of bleeding and necessitates caution for the use and choice of anticoagulant therapies. LMWH, dalteparin and tinzaparin, are relatively safe, although not completely without risk.  On the other hand, a higher risk of bleeding has been reported in patients with gastrointestinal tumors treated with direct factor Xa inhibitors, such as edoxaban and rivaroxaban [16-17-18].

Generally, in patients with renal impairment, it is necessary to adjust the dosage of anticoagulants to avoid the risk of bioaccumulation and consequent risk of bleeding with exception of tinzaparin [1-19].

Extended anticoagulant treatment is recommended if the cancer is active, if the primary tumor is present, and if patients are undergoing continuous treatment for metastatic disease. Apparently, the risk of major bleeding is not increased when treatment is continued, while offering the benefit of reducing VTE recurrences [20]. Regarding catheter-related VTE, it is reported that peripherally inserted central catheters (PICCs) carry a higher risk of venous thromboembolic events as compared with totally implanted ports (PORTs) [21]. Once catheter-associated venous thrombosis occurs, the guidelines recommend an anticoagulant treatment for a minimum of three months.

Conclusions

In conclusion, CRC ranks among the top ten cancers associated with CAT. The clinical conditions and characteristics of CRC patients significantly influence the choice of treatment for VTE. In fact, certain drugs used in advanced settings, such as vascular angiogenic inhibitors, can favor the occurrence of CAT. Furthermore, the ESMO clinical practice guidelines can serve as a valuable resource for clinicians managing CAT.

Watch De Stefano’s lecture:

References

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