Locally advanced NSCLC associated with increased risk for VTE

Patients with locally advanced non–small cell lung cancer are at a high risk for venous thromboembolism, particularly within the first year after treatment initiation, according to a retrospective risk analysis.

The risk for VTE with malignancy appears highest among patients with lung cancer. Clinical predictors for VTE include race, receipt of surgery and chemotherapy, receipt of VEGF inhibitors and advanced stage of disease.

Histologic subtype also appears to be an independent factor of a higher risk for VTE in patients with NSCLC compared with small cell lung cancer.

Previous studies have evaluated highly heterogeneous populations of patients with varying stages of lung cancer; however, a focus on locally advanced NSCLC — which is associated with poor prognosis despite aggressive treatment — does not exist.

Raymond Mak, MD, assistant professor of radiation oncology at Brigham and Women’s Hospital/Dana-Farber Cancer Institute, and colleagues evaluated 629 patients (median age, 64 years; 48% male) with stage II to III NSCLC treated with radiation therapy to estimate the risk for VTE and the associated clinical predictors in the locally advanced cohort.

The development of pulmonary embolus or deep vein thrombosis served as the primary endpoint.

Ninety percent of patients reported to be current or former smokers, 51% of patients had adenocarcinoma and 30% of patients had squamous cell carcinoma.

At diagnosis, 11% of patients presented with stage IIA or IIB disease, 56% with stage IIIA disease and 33% with stage IIIB disease. Further, nodal staging revealed 24% of patients had N0 or N1 disease, 52% had N2 disease and 24% had N3 disease.

Median follow-up was 31 months.

Researchers recorded a total of 127 VTE events for a crude risk of 78 per 1,000 person-years. Fifty-one patients (40%) experienced DVT, 56 (44%) experienced PE and 20 (16%) had both DVT and PE.

Most of the events (76%) occurred prior to the development of distant metastasis. Eighty percent of events occurred within 1 year after the start of treatment — 55 events occurred during active treatment and 47 events occurred after treatment.

“When evaluating patients with locally advanced NSCLC, clinicians should be aware that VTE has a high incidence and often presents with limited symptoms,” Mak and colleagues wrote. “Furthermore, VTE was often diagnosed before or during a course of radiation therapy or chemotherapy, which underscores the need for medical and radiation oncologists to vigilantly monitor for signs and symptoms even during routine ambulatory visits throughout combined modality therapy, and to maintain a low threshold to perform further imaging workup.”

The researchers used a Fine and Gray’s competing regression model to identify significant predictors for VTE risk, with death and distant metastasis accounted for as competing risks.

The first failure event was VTE in 97 patients, distant metastasis in 288 patients and death in 94 patients.

Results showed an overall 1-year cumulative VTE incidence of 13.5% and an overall 3-year cumulative VTE incidence of 15.4%.

In a univariate analysis, overall stage IIIB disease significantly increased VTE risk compared with stage IIA to IIIA disease (HR = 1.49; 95% CI, 12.24). The 1year cumulative incidence of VTE was 17.4% (95% CI, 12.622.9) in patients with stage IIIB disease compared with 11.7% (95% CI, 8.814.9) in patients with stage IIA to IIIA disease. The 3year cumulative incidence also was higher in patients with stage IIIB disease (19.4% vs. 13.4%).

Further, N3 nodal disease was associated with increased VTE risk compared with N0 to N2 disease (HR = 1.55; 95% CI, 1.012.38). Patients with N3 disease had higher 1year cumulative incidence (19.1% vs. 11.8%) and 3year cumulative incidence (20.4% vs. 13.8%) of VTE.

The final multivariable model demonstrated that N3 nodal disease was associated with greater VTE risk (HR = 1.64; 95% CI, 1.062.54).

“Future studies of thromboprophylaxis in locally advanced NSCLC should consider selection of patients with more extensive nodal disease,” Mak and colleagues wrote.

Patients with VTE events that occurred in the first year after treatment initiation also showed shorter OS compared with patients who did not have a VTE event in the first year (P = .018); however, there was no difference in PFS.

The researchers acknowledged the study was limited by its retrospective nature and its limit to definitive radiation therapy.

“A clear consensus for the role of thromboprophylaxis in ambulatory lung cancer patients requires further study to strengthen the evidence base,” the researchers wrote. “Identifying a highrisk cohort that may be the focus for future studies and eventual guidelines.” – by Kristie L. Kahl

Disclosure: The researchers report no relevant financial disclosures.