The early and long-term occurrence of symptomatic venous thromboembolism after lung cancer surgery without extended thromboprophylaxis—a single center experience with 435 patients

Introduction

Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in cancer patients, contributing to significant morbidity and mortality (1-4). Approximately 20% of all VTE cases may be attributed to cancer (5), and cancer patients experience more than three times higher mortality rates when compared to non-cancer controls (6). The management of VTE in cancer patients is challenging, often requiring long-term anticoagulation that increases the risk of bleeding. Additionally, recurrent VTE despite anticoagulant therapy is more frequent in patients with cancer (7).

In patients with lung cancer, the overall incidence of thromboembolic complications is high with an estimated rate of 39.2 per 1,000 person-years, surpassing the average incidence of thromboembolic complications in patients with cancer (8). Notably, VTE following lung cancer surgery is associated with an eight-fold increase in mortality rates which is higher than following other types of major cancer surgeries (9). However, the reported incidence of VTE in surgically treated lung cancer patients varies widely across the literature. A comprehensive systematic review encompassing 19 trials and 10,600 patients estimated the mean occurrence of VTE to be 2.0% during an average observation period of 16 months (10). Most studies have limited follow-up periods, predominantly focusing on immediate post-operative months, and studies with longer-term follow-up are scarce. Furthermore, variations in thromboembolic protocols and diagnostic methods for detecting thromboembolic events further complicate the interpretation and comparison of findings between studies.

Therefore, the aim of the study was to investigate both the early and long-term occurrence of VTEs in lung cancer patients undergoing curative-intent surgery. Additionally, the study aimed at identifying patient-specific risk factors associated with VTE. To facilitate comparisons with the expected rate of VTE in the general population, particularly during long-term follow-up, the rates were compared to those of a demographically matched reference population. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-308/rc).

Methods

Study patients and reference population

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Pirkanmaa Hospital District, Tampere, Finland (No. R17575) and individual consent for this retrospective analysis was waived. The study population included all patients who underwent lung cancer surgery between February 2004 and December 2016 in the Tampere University Hospital, Tampere, Finland. The study hospital is a tertiary academic referral center and the second largest hospital in Finland with a catchment area exceeding 1 million residents. The patients were identified from the institutional database by retrieving all cases associated with the Nordic Medico-Statistical Committee (NOMESCO) Classification of Surgical Procedure codes for sublobar resections, lobectomies of one or more lung lobes, bronchial resections, as well as pneumonectomies. Each case was carefully reviewed and patients without histopathological confirmed lung cancer in the final analyses and those who did not undergo planned resections due to advanced disease stage observed during surgery were excluded. Relevant demographic information, medical history including possible data on neoadjuvant treatments, cancer stage and histopathology were collected from each patient. Data on surgical technique and extent of the surgery, recovery, including the length of hospitalization and the occurrence and types of complications, were recorded. The demographically matched reference population was obtained by requesting a random sample of 10 individual controls for each patient that were matched for sex, age and the location of residence, from the Finnish Population Register Centre, a national registry that also provides large control materials for research purposes, from which survival data was also obtained for both the patients and the reference population. The follow-up period for individuals in the reference population commenced at the matching date to that of their corresponding patients’ date of surgery. The follow-up included all deaths occurring until December 31^st, 2018.

Thromboembolic complications

Over the study period the standard clinic practice for pharmacological thromboprophylaxis involved daily subcutaneous injections of low-molecular-weight heparin (enoxaparin 40 mg) during hospitalization. Deviations from this protocol (e.g., in cases with bleeding or in those with oral anticoagulants) were at the discretion of the treating clinician. Information regarding subsequent thromboembolic events, specifically DVT or PE, in both study cohorts were obtained from the National Institute for Health and Welfare database that contains complete data on all specialized medical care hospitalizations as well as emergency room and outpatient clinic visits in Finland. Treatment episodes associated with the 10^th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis codes “I80”, “I82”, or “I26”, or any subclass of these diagnosis codes, following the date of the lung cancer surgery in patients and the corresponding index date in controls were identified from the database and classified as having DVT and/or PE for the purposes of the study. The follow-up lasted until the end of December 2016. The occurrence, type, and timing of VTE, and the number of related in-hospital days as well as patient-specific risk factors and overall long-term survival were ascertained using statistical methods. The occurrence of VTE and the survival rates were similarly compared to those of the reference population.

Statistical analyses

Statistical analyses were carried out using IBM SPSS Statistics version 28 statistical software for Windows (IBM Corp. Armonk, NY, USA). The cumulative occurrence and type of venous thromboembolism were compared between patient subgroups and between patients and the reference population at pre-determined time points. Any study participant, who did not complete the full follow-up period due to inadequate follow-up time or death were excluded from the relevant analyses at each time point, unless they had already experienced a venous thromboembolic event. Comparative analyses between the two groups were performed using Fisher’s exact and χ² tests for categorical variables and Mann-Whitney U test for nonparametric continuous variables. Kaplan-Meier curves and the log rank test were used to illustrate and compare the occurrence of venous thromboembolic events in patients and the reference population. Statistical significance was set at P<0.05.

Results

The study included a total of 435 surgically treated lung cancer and 4,338 matched controls comprising the reference population. Nine patients were excluded from the analysis due to unavailable registry follow-up data due to, for example, expatriation or prohibitions regarding the individual’s registry data use. For two patients there were fewer than 10 available controls, and the cases were included in the analysis. The median follow-up time for the patients and the reference population was 70 (range, 0–154) months. The cumulative total number of person-months followed-up was 30,478 for patients and 302,956 for the reference population. Altogether 150 patients and 2,101 controls completed the full 5-year follow-up. Table 1 presents the demographic information of the study population, the histology, and the stage of lung cancer at the time of operation, patient comorbidities, types of surgeries performed, and clinical details regarding the postoperative course. Adenocarcinoma was the most common histology of lung cancer, accounting for 51.5% of all cases, and more than half of all cases (58.2%) were classified as stage I lung cancers. The majority of patients (73.1%) underwent open surgery, while the rest had video-assisted thoracic surgical procedures, and 12.6% required reoperations, primarily due to persistent air leak, infections, and bleeding. The median duration of postoperative hospitalization following lung cancer surgery was 5 (range, 1–53) days during the study period.

Table 2 and Figure 1 present the main results of the study. The cumulative occurrence of VTE in patients who underwent lung cancer surgery was significant, reaching 18.7% at 5 years, compared to a rate of 3.9% in the reference population. Most VTEs were PE. The occurrence of VTEs appeared to gradually increase over the follow-up period, initially showing no statistically significant difference between patients and the reference population. No statistically significant associations were found between patient characteristics and the occurrence of VTEs during follow-up (Table 3). There were no associations with the surgical technique or the extent of surgery with later thromboembolic complications. Mortality rates for patients and the reference population are shown in Table 4, and the numbers of in-hospital days related to VTEs during follow-up are shown in Table 5.

Figure 1 The cumulative occurrence of venous thromboembolic events in the patients and in the reference population.

Discussion

Patients with lung cancer are known to be at high risk for thromboembolic complications, and VTE has been associated with worse outcomes and early mortality in these patients (11-13). Surgery further increases the risk of thromboembolic events due to prolonged bed rest, reduced ambulation, and activation of platelets and the coagulation cascade (14,15). Furthermore, patients receiving surgery for malignant disease are in higher risk for developing thromboembolic complications than other surgically treated patients (9,16). In addition to a higher recurrence rate of VTE in cancer patients despite anticoagulation, these patients also seem to suffer from an increased risk of bleeding events during follow-up (7). A previous study from the COMMAND VTE registry showed that major bleeding events are common during anticoagulation therapy in cancer patients treated for VTE, and in their study population, 13% of lung cancer patients treated for VTE developed a major bleeding during follow-up (17). Consequently, in addition to analyzing the risks associated with VTE, morbidity due to bleeding events must also be regarded when considering the duration of postoperative anticoagulation. The present study demonstrates that the occurrence of symptomatic thromboembolic complications, particularly PE, among patients undergoing lung cancer surgery is significant, especially during long-term follow-up. Furthermore, VTE and the related in-hospital treatment episodes in these patients appear to inflict a substantial burden and consequently costs for the health care system, as also shown in earlier literature (18).

Surprisingly, the occurrence of VTE was not significantly elevated during the early post-operative period. Instead, the episodes occurred gradually over the entire follow-up period, which differs somewhat from previous studies suggesting that the highest risk for thromboembolic complications is during the initial postoperative period (10,12,13,19-22). Consistent with our study, a recent retrospective analysis conducted by Akhtar-Danesh et al. (23) in a cohort of 12,626 patients, who underwent lung cancer surgery between 2005 and 2013, reported postoperative incidences of VTE at 90 days and one year to be 1.31% and 2.73%, respectively, in patients not subjected to routine VTE screening. In a study by Thomas et al. (12), comprising a large cohort of 14,308 patients treated between 2005 and 2015, the prevalence of VTE was 1.6% at 30 days and 44% of thromboembolic events occurred after hospital discharge. Another retrospective study by Hachey et al. (20) reported an overall 60-day incidence of VTE of 5.2% in a cohort of patients treated between 2005 and 2013 who received in-hospital thromboprophylaxis and were not routinely screened for VTE. To the best of the authors’ knowledge, the present study is the first to report the occurrence of VTE during extended follow-up in this patient group. The authors speculate that a major reason for the high occurrence of VTE during extended follow-up may be due to the significant risk for cancer recurrence in this patient group which unfortunately occurs relatively frequently (24,25) and is also reflected in the comparatively high mortality rates during follow-up.

Extended pharmacologic thromboprophylaxis has been proven to be effective in reducing postoperative VTE in major abdominal or pelvic oncological surgery (26). However, the optimal duration of thromboprophylaxis for lung cancer surgery remains uncertain. Current guidelines offer varying recommendations: the American College of Chest Physicians suggests in-hospital routine thromboprophylaxis for thoracic surgery patients (27), the European Society of Anesthesiology advocates for pharmacological prophylaxis alongside intermittent pneumatic compression without specifying the duration (28), and the American Society of Clinical Oncology and European Society for Medical Oncology recommend continuing thromboprophylaxis for 7–10 days post-surgery (29,30). Recently, evidence-based guidelines by The American Association for Thoracic Surgery and the European Society of Thoracic Surgery propose parenteral anticoagulation combined with mechanical methods for VTE prevention in patients undergoing surgery for lung cancer, during hospitalization in low-risk patients, and extended prophylaxis for 28–35 days for moderate or high-risk patients and for those undergoing pneumonectomies (31). However, an international survey involving members of various thoracic surgery associations reported that extended thromboprophylaxis is not routinely prescribed after lung cancer surgery (32).

Interestingly, in a recent single-center prospective study from China, in which no routine perioperative thromboprophylaxis after lung cancer surgery was utilized, the reported incidence rate for VTE reached 15% (33). In turn, Kho et al. recently studied the impact of extended thromboprophylaxis employed 28 days postoperatively in patients undergoing lung cancer surgery and the authors reported a significant reduction in PE, 4.0% vs. 0.4%, during a 6-month follow-up with active screening (34). A significant proportion of VTEs are asymptomatic or have symptoms that may be mistaken for those expected to occur postoperatively, and studies with active postoperative VTE screening have demonstrated an increased prevalence of VTE after lung cancer surgery, up to 12.1% (13,19).

This study did not find any patient or surgical technique-related risk factors, such as advanced age, cancer stage, neoadjuvant therapy or extensive surgery for VTE, likely due to the relatively small number of VTE events and limited statistical power. Other studies have identified several risk factors for thromboembolic complications including advanced age, obesity, advanced cancer stage, and pneumonectomy (12,22,23). The long-term mortality rates observed in the present study are similar to those described in the current literature, for example a report from the Danish Lung Cancer Registry showed 90-day and 1-year mortalities of 4.6% and 14.2%, respectively, and the 5-year survival rates were also comparable to the results published by others (35).

There are several limitations regarding the study. The material is complete but consists of patients treated at a single university hospital and may not accurately reflect the patient material at other institutions. Our results portray the rate of thromboembolic complications when only in-hospital thromboprophylaxis was used. Also, the retrospective setting of this study causes some limitations regarding the availability of some patient’s medical history data limiting subgroup analyses. While information regarding the comorbidities of the reference population was not available, due to their large number, the reference population should accurately reflect the standard population with typical rates of comorbidities and similar age- and sex-distributions than those of the patient material. Furthermore, the proportion of patients that were prescribed on oral or other anticoagulation during follow-up is not known. The rate of thromboembolic complications observed in the present study probably reflects only the symptomatic cases as no routine screening was performed, possibly underestimating the true incidence of VTEs. Despite this, the odds of experiencing symptomatic VTE in patients were approximately five times higher when compared to the reference population over long term follow-up. Furthermore, the rate of DVT was relatively low in the patients, possibly because when concomitant DVT and PE were present only the diagnosis code of PE may have been used, and because DVTs may have been diagnosed and treated in primary health care. The exact methods by which venous thromboembolism was diagnosed and disease severity could not be controlled.

The proportion of patients undergoing video-assisted thoracic surgery (VATS) increased during the study period causing heterogeneity in the patient material. The strengths of the study include a large cohort of patients treated over a time period of nearly two decades with extensive follow-up time, the robust and inclusive registry data available in Finland, as well as the presence of a reference population.

Conclusions

In conclusion, the authors report that patients undergoing lung cancer surgery, and who receive medical thromboprophylaxis during the hospitalization, do not seem to be in higher risk for thromboembolic complications during the initial postoperative period and short-term follow-up. However, during long-term follow-up the occurrence of symptomatic thromboembolic complications, particularly PE, was statistically significantly higher than in demographically matched controls. No clear patient-specific risk factors associated with the development of VTE were identified.

Acknowledgments

Funding: This study was supported by grants from the Tampere Tuberculosis Foundation, the Foundation of the Finnish Anti-Tuberculosis Association, the Väinö ja Laina Kiven säätiö and the Finnish Cultural Foundation.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-308/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-308/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-308/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-308/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Pirkanmaa Hospital District, Tampere, Finland (No. R17575) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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