In the present study, we examined the relationship between prophylactic anticoagulation during chemotherapy and incidence of VTE events as well as the association between prophylactic anticoagulation and overall survival of GCT patients treated with first line chemotherapy. In order to assess the effect of prophylactic anticoagulation on the incidence of VTE events, we included only events occurring during first-line chemotherapy, when patients were also receiving LMWH prophylaxis.
We have observed that most VTE events occur even before the initiation of chemotherapy. There was a 4% incidence of VTE events occurring during chemotherapy. Observed incidence of VTE events is in line with the incidences reported in the literature.[6, 8, 10, 17-19] However, there is a wide variation in the reported incidences. While the lowest reported incidence is 2%, in a different study, there was 23.7% incidence of thromboembolic events.[8, 19] A significant part of this variation is probably caused by different inclusion criteria: including arterial events, including patients with VTE events before the start of chemotherapy, and events occurring several months after chemotherapy. Small number of patients some studies may also contribute to this variability.
We have observed no significant differences in VTE incidence between patients with and without LMWH prophylaxis. While there have been several studies assessing VTE incidence and identifying VTE risk factors in GCT patients, most of them included only a small number of the study patients with LMWH prophylaxis. Solari et al. compared the incidence of thromboembolic events in patients receiving limited and extended LMWH prophylaxis. Limited prophylaxis was administered only during hospitalization. Extended prophylaxis was administered daily from the first day of the first cycle to day 21 of the last cycle of chemotherapy. They did not observe significant differences between these two groups. However, their study did not include a control group with no prophylaxis and therefore the effect of LMWH prophylaxis cannot be assessed. Paradoxically, the incidence of thromboembolic events reported in their study (23.7%) was much higher than in other studies.[19] However, arterial events were also included in their analysis. Gizzi et al also compared the VTE incidence in GCT patients with and without LMWH prophylaxis. In their study, prophylaxis was administered to a subgroup of patients with risk factors for VTE (elevated lactate dehydrogenase or high body surface area). They have observed no statistically significant difference in VTE incidence between the two groups. However, neither the type of LMWH used nor the dosing of prophylaxis are mentioned.[12]
Unexpectedly, there was a trend to shorter overall survival in our patients who received LMWH prophylaxis. On further analysis we found a significantly shorter overall survival in patients receiving LMWH prophylaxis with NSGCT histology or extragonadal tumor location.
Prospective study assessing the effect of prophylactic anticoagulation in patients with GCT receiving chemotherapy compared to no prophylaxis is lacking. However, the data available suggest that LMWH prophylaxis does not offer the expected benefits in terms of decreased incidence of VTE events in GCT patients.[12, 19] On the contrary, our data suggest that administering LMWH prophylaxis might confer a higher risk for treatment related deaths in patients with extragonadal tumors. Given the small number of patients with extragonadal tumors included in our study and selection bias, this result is only hypothesis generating. Further research should focus on examining the possible association between LMWH and increased incidence of TRDs. In October 2019, American Society of Clinical Oncology published an updated guideline on the use of thromboprophylaxis in cancer patients. According to this guideline, hospitalized patients with active malignancy without additional risk factors may be offered pharmacologic thromboprophylaxis. However, routine use of thromboprophylaxis in cancer patients hospitalized solely for administration of chemotherapy is no longer recommended.[20]
To the best of our knowledge, this is the largest study evaluating the effect of LMWH prophylaxis on VTE incidence in GCT patients receiving chemotherapy. Our study has several limitations. First of all, LMWH prophylaxis was not random, possibly causing selection bias. It is possible that patients at higher risk for VTE were given thromboprophylaxis more frequently what could in turn obscure the effect of thromboprophylaxis. However, incidence of VTE in patients without prophylaxis before 2010 was similar to incidence of VTE in subgroup of patients with prophylaxis after 2010, totally as well as in subgroup analysis based on IGCCCG risk group (Supplementary Table S1). This support the conclusion of no beneficial effect of prophylaxis in GCTs patients. Secondly, the study has retrospective design. Some VTE events could have been missed as a result of incomplete medical records.