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Keywords:

  • anticoagulation;
  • epidemiology;
  • incidence;
  • lung cancer;
  • outcomes;
  • thromboembolism

Summary.

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflict of Interests
  9. References

Background: The incidence of venous thromboembolism (VTE) by lung cancer histology and stage is unknown. Objectives: To determine the incidence of VTE and the risk factors associated with development of VTE in a large population-based study of patients with non-small cell and small cell lung cancer. Methods: The California Cancer Registry was merged with the Patient Discharge Data Set to determine the incidence of VTE among lung cancer cases diagnosed between 1993 and 1999. Results: Among 91 933 patients with newly diagnosed lung cancer, the 1-year and 2-year cumulative VTE incidences were 3.0% and 3.4%, respectively, with a person-time rate of 7.2 events/100 patient-years during the first 6 months. The 1-year incidence of VTE was significantly increased in comparison to the general population [standardized incidence ratio = 21.2, 95% confidence interval (CI) = 20.4–22.0]. In a multivariate model, significant predictors of developing VTE within 1 year of non-small cell lung cancer (NSCLC) diagnosis were: younger age, the number of chronic medical comorbidities [hazard ratio (HR) = 2.8 if 3 vs. 0, 95% CI = 2.5–3.1], advancing cancer stage (HR = 4.0 for metastatic vs. local disease, 95% CI = 3.4–4.6) and adenocarcinoma histology (HR = 1.9 vs. squamous cell, 95% CI = 1.7–2.1). In multivariate models, VTE was a significant predictor of death within 2 years for both NSCLC and small cell lung cancer (SCLC), HR = 2.3, 95% CI = 2.2–2.4, and HR = 1.5, 95% CI = 1.3–1.7, respectively. Conclusions: Approximately 3% of lung cancer patients developed VTE within 2 years. The diagnosis of VTE was associated with a higher risk of death within 2 years for NSCLC and SCLC.


Introduction

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflict of Interests
  9. References

Among solid tumors, lung cancer and tumors of the gastrointestinal and genitourinary tract have been reported to have a high incidence of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Data on Medicare patients revealed a rate of DVT/PE among lung cancer of 61/10 000 patients [1] and a relative risk of 1.1 as compared to non-cancer patients [2]. Data from the National Hospital Discharge Survey revealed a VTE incidence of 2.1% among lung cancer patients, as compared with 1% in hospitalized patients without cancer [3]. A population-based control study of VTE reported an odds ratio of 22 in lung cancer patients as compared to cases without malignancy [4]. These previous studies did not stratify patients by histology, cancer stage, or treatment. We recently reported the incidence of VTE among patients with commonly diagnosed cancers using the California Cancer Registry merged with the state’s Patient Discharge Data Set. The 2-year cumulative incidence of VTE among patients with metastatic lung cancer was 2.4%, with a rate of five VTE cases per 100 patient-years [5]. However, a detailed analysis of the effects of histology, comorbidities and cancer-related surgery was not performed.

More intriguing than the elevated incidence of VTE among lung cancer patients are the clinical trials of anticoagulation in addition to chemotherapy that suggest a survival benefit among those with small cell lung cancer (SCLC) [6–9], implying that disruption of the procoagulant pathway may improve cancer outcomes. Furthermore, a recent autopsy study and an analysis of patients undergoing thoracotomy reported a higher incidence of thromboembolism among those with adenocarcinoma than among those with other lung cancer histologies [10,11]. Similarly, a lung cancer cohort study concluded that patients with adenocarcinoma had a 3-fold higher risk of VTE than patients with squamous cell histology [12]. These reports suggest that among patients with non-small cell lung cancer (NSCLC), adenocarcinoma may be a risk factor for the development of VTE.

The objectives of the current study were to describe the incidence and time course of VTE in a population-based cohort with newly diagnosed, histologically confirmed and pathologically staged lung cancer, and to determine risk factors and outcomes associated with the development of VTE. Because NSCLC and SCLC are staged and treated distinctly, the analyses were performed separately.

Methods

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflict of Interests
  9. References

Databases

This study was conducted using two merged databases, the California Cancer Registry and the California Patient Discharge Data Set, which have been previously described [5,13]. The Cancer Registry records information on all cancers diagnosed in California. The Discharge Data Set includes discharge diagnoses and procedure codes on all hospitalizations in California, except those in a federal or military hospital. This study was approved by the California Health and Welfare Agency Committee for the Protection of Human Subjects and the UC Davis Human Subjects Committee.

Lung cancer cohort

The lung cancer cohort included all lung cancer cases diagnosed in individuals 18 years or older between January 1993 to December 1995 and January 1997 to December 1999. These dates were selected because, during this time period, outpatient use of low molecular weight heparin was rare, and patients with symptomatic VTE required hospitalization. Cases diagnosed at federal or military hospitals (= 14) were excluded because of the absence of hospital discharge data. Registry information included basic demographics, the Surveillance, Epidemiology, and End Results (SEER) cancer stage, date of diagnosis, type and extent of major surgery, and cancer histology. Tumor histology was categorized as NSCLC or SCLC. Within NSCLC, histology was further divided into adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and carcinoma not otherwise specified (NOS). Histological types with fewer than 25 cases, sarcomas and carcinoid tumors were excluded. SEER stage 1 is localized, being confined to the lung; SEER stages 2–5 are regional, involving ipsilateral lymph nodes, direct extension, or both; and SEER stage 7 is remote, involving distant metastasis. Within SCLC, stage was categorized as limited (localized and regional) or extensive (remote). The date of cancer diagnosis was defined as the earlier of: (i) the cancer registry diagnosis date; or (ii) the date of a hospital admission that included an ICD-9-CM for primary or metastatic lung cancer.

Outcomes

The primary outcomes were the incidence of VTE and survival. Death was determined using the California master death registry linked to the Patient Discharge Data Set. DVT and PE were defined using previously validated ICD-9-CM codes 451.1×, 451.2, 451.81, 453.1, 453.2, 453.8, 453.9 and 415.1× in the principal or a secondary position together with a hospital stay of 2 or more days, unless the patient died. Cases with superficial phlebitis or upper extremity VTE were identified but excluded in the primary analysis. To identify only first-time VTE cases, records with a VTE diagnosis between 1 July 1990 and the date of lung cancer diagnosis were excluded.

Time and classification of VTE events

The date of admission was considered the date of the VTE event for cases admitted with a principal diagnosis of VTE. If VTE was a secondary diagnosis and there was an associated code for a test to diagnose VTE, the VTE date was the procedure date. For cases with a secondary diagnosis of VTE and no test date, the VTE diagnosis date was assigned the median day of hospitalization [14].

Standardized incidence ratio (SIR) of VTE

In a prior study [15], the crude age-, race- and sex-specific incidence of first-time VTE in California between 1995 and 1997 was determined using the California Patient Discharge Data Set and the identical ICD-9-CM codes and exclusion criteria used in the present study to define VTE. The 2000 census figures for age, race, and sex were used to define the population distribution, adjusting the total population to published estimates for 1995–1997 [16]. The age, race, and sex distribution of the cancer cohort that was alive at the 6-month midpoint following lung cancer diagnosis was used to calculate the expected incidence of VTE in 1 year.

Comorbidity

The presence of chronic comorbid medical conditions was determined using a variation of the Elixhauser comorbidity index Version 3.0 (http://www.hcup-us.ahrq.gov/toolssoftware/comorbidity/comorbidity.jsp#download), a comorbidity measure designed for use with large administrative inpatient datasets [17]. Of the 29 conditions defined by this index, five conditions were excluded, three terms for cancer (tumor, metastatic, lymphoma) and two terms for acute conditions (electrolyte disturbance, coagulopathy). The number of chronic comorbid conditions was based on diagnosis codes and diagnostic-related group codes present during either the index hospitalization or any hospitalizations within 2 years of the cancer diagnosis [18].

Statistics

Incidence rates were calculated as both cumulative incidence and as person-time (events/100 patient-years). SIRs of VTE were calculated and confidence intervals (CIs) were computed assuming an underlying Poisson distribution for the number of VTE events. Cox proportional hazard models were used to analyze the effect of specified risk factors on the outcomes of VTE or death within 2 years of cancer diagnosis. In models predicting death, VTE was entered as a time-dependent covariate, as was major surgery in models predicting VTE. The significance of individual levels of polytomous variables was only interpreted following an overall test of significance using Type III Sums of Squares tests. Proportionality assumptions of the models were checked and were met by the data. Kaplan–Meier plots were generated to compare survival among cases that developed VTE to that among cases that never developed VTE, matching four controls to each case on survival from the cancer diagnosis date to the VTE diagnosis date, age (within 1 year), race (Asian vs. non-Asian), and cancer stage. Analyses were performed using SAS, S-plus, or SISA (http://home.clara.net/sisa/smr.htm; accessed 30 January 2008). Given the large sample size, in multivariate models and comparisons of survival, < 0.0001 was used to define statistical significance.

Results

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflict of Interests
  9. References

In total, 91 933 eligible lung cancer cases were identified in the 6-year study period. As shown in Table 1, 46% of cases were female, the average age was 69 ± 12 years, and Caucasians made up 79% of the cancer cohort. Eighty-five percent of the cancers had NSCLC histology and 15% had SCLC histology. Fifty-one percent were initially diagnosed with metastatic disease.

Table 1.   Incidence of venous thromboembolism (VTE) based on demographic and clinical characteristics
VariableNumber of cases (%)Rate of VTE per 100 patient-yearsTwo-year cumulative incidence of VTE, n (%)% alive at
0–6 months7–12 months1 year2 years
  1. NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer. *Eight cases with unknown gender are not included. <1% of the cohort classified as ‘other’ are not included. Expressed as total of NSCLC histology.

Total cases91 9337.22.43140 (3.4)3621
Female*42 449 (46)7.12.41478 (3.5)3924
Male*49 476 (54)7.32.41662 (3.4)3319
Age groups
 <45 years2002 (2)11.94.1131 (6.5)4122
 45–64 years26 957 (29)8.52.91223 (4.5)4226
 65–74 years32 879 (36)6.82.21082 (3.3)3823
 ≥75 years30 095 (33)6.01.8704 (2.3)2715
Race
 Caucasian72 928 (79)7.52.52578 (3.5)3621
 Hispanic6661 (7)7.22.1216 (3.2)3419
 African American6482 (7)7.62.5232 (3.6)3520
 Asian American5584 (6)3.71.4109 (2.0)4025
NSCLC histology78 391 (85)7.72.42801 (3.6)3722
 Adenocarcinoma30 852 (39)9.92.91550 (5.0)4430
 Squamous cell carcinoma18 426 (24)4.81.6471 (2.6)4325
 Large cell carcinoma5976 (8)6.62.5193 (3.2)3319
 Carcinoma NOS23 137 (29)7.32.3587 (2.5)2311
NSCLC stage
 Localized12 625 (16)2.71.1274 (2.2)7559
 Regional15 084 (19)4.92.2513 (3.4)5534
 Metastatic38 264 (49)13.24.11806 (4.7)198
 Unknown12 418 (16)3.71.9208 (1.7)3016
SCLC histology13 542 (15)4.52.3339 (2.5)3313
SCLC stage
 Limited3557 (26)3.71.794 (2.6)5426
 Extensive8566 (63)5.12.6206 (2.4)226
 Unknown1419 (11)4.03.139 (2.7)4219

The 1-year and 2-year cumulative incidences of VTE were 3.0% and 3.4%, respectively among the entire lung cancer cohort. Table 1 summarizes the incidence of VTE, expressed both as the rate of VTE per 100 patient-years in the first and second 6 months after cancer diagnosis, and as the 2-year cumulative incidence of VTE. Survival at 1 and 2 years after diagnosis is shown. The rates of VTE among the entire cohort in the first and second 6 months after cancer diagnosis were 7.2 and 2.4 cases per 100 patient-years, respectively. For each gender, age group, race, histological subtype, and cancer stage, the incidence rate of VTE was highest in the first 6 months after cancer diagnosis. The incidence of VTE was highest among cases younger than 45 years, with 12 VTE cases per 100 patient-years in the first 6 months, and decreased with increasing age. Among those with NSCLC, the rate of VTE was highest in patients with adenocarcinoma histology and increased among all those with NSCLC with advancing stage. Among those with SCLC, the rate of VTE per 100 patient-years also increased with extensive stage.

The SIR of VTE during the first year of follow-up is shown in Table 2. The SIR for the entire lung cancer cohort was 21.2 (95% CI = 20.4–22.0). Among those with NSCLC and SCLC, the SIRs were 22.3 (95% CI = 21.4–23.2) and 14.4 (95% CI = 12.8–16.1), respectively.

Table 2.   Standardized incidence ratios (SIRs) of venous thromboembolism (VTE) during the first year following lung cancer diagnosis
Lung cancer cohort (n)VTE observed in year 1VTE expected in year 1 SIR (95% CI)
  1. CI, confidence interval. *< 0.001.

Total, 91 933280213221.2 (20.4–22.0)*
Non-small cell cancer, 78 391251511322.3 (21.4–23.2)*
Small cell lung cancer, 13 5422872014.4 (12.8–16.1)*

The results of a multivariate analysis of potential risk factors associated with the development of VTE within 1 year after diagnosis of NSCLC or SCLC are shown in Table 3. Among those with NSCLC, factors associated with a significantly higher risk of VTE included younger age, increasing number of chronic comorbid conditions, advancing cancer stage, and adenocarcinoma histology. Asian ethnicity and lung cancer-related surgery were associated with significantly lower risks of developing VTE. Among SCLC, increasing numbers of comorbidities was the only significant risk factor associated with VTE. Gender was not a significant factor for VTE among those with NSCLC or SCLC.

Table 3.   Effect of sex, age, race, comorbidities, initial cancer stage, histology and surgery on the development of venous thromboembolism (VTE) within 1 year of lung cancer diagnosis
VariableNon-small cell lung cancerSmall cell lung cancer
Hazard ratio for VTE (95% CI) P-valueHazard ratio for VTE (95% CI) P-value
  1. CI, confidence interval. *Small cell lung cancer stages were limited (localized and regional) and extensive. Not evaluated, due to small numbers of patients who had surgery.

Sex (vs. male)1.0 (0.9–1.1)0.91.0 (0.8–1.3)0.9
Age (vs. <45 years)
 45–64 years0.7 (0.6–0.9)0.0010.8 (0.4–1.6)0.5
 65–74 years0.6 (0.5–0.7)<0.00010.7 (0.3–1.5)0.4
 >75 years0.5 (0.4–0.6)<0.00010.6 (0.3–1.2)0.1
Race (vs. Caucasian)
 Black0.8 (0.7–0.9)0.0011.1 (0.7–1.7)0.7
 Hispanic0.8 (0.7–0.9)0.0031.0 (0.6–1.6)0.9
 Asian American0.4 (0.4–0.5)<0.00010.7 (0.3–1.4)0.3
Number of chronic comorbid conditions (vs. 0)
 12.0 (1.8–2.2)<0.00011.9 (1.4–2.6)<0.0001
 22.4 (2.2–2.7)<0.00012.1 (1.5–2.9)<0.0001
 32.8 (2.5–3.1)<0.00012.4 (1.7–3.3)<0.0001
SEER stage (vs. localized)
 Regional1.9 (1.6–2.2)<0.0001* 
 Metastatic4.0 (3.4–4.6)<0.00011.3 (1.0–1.7)0.06
Histological subtype (vs. squamous cell carcinoma)
 Adenocarcinoma1.9 (1.7–2.1)<0.0001  
 Large cell carcinoma1.2 (1.0–1.4)0.08  
 Carcinoma NOS1.2 (1.1–1.4)0.002  
Lung-related surgery
 Yes vs. No0.7 (0.6–0.8)<0.0001Not evaluated 

Figure 1A,C shows Kaplan–Meier plots of the 2-year incidence of VTE among patients with NSCLC and SCLC. In these plots, the day of VTE diagnosis was assigned as day 0 if the VTE was diagnosed during the same hospitalization as the cancer diagnosis. Figure 1A,B shows the incidence of VTE among those with NSCLC and SCLC, respectively, stratified by stage. The incidence of VTE increased with advancing stage in patients with NSCLC and, to a lesser extent, among those with SCLC. For both NSCLC and SCLC, the incidence of VTE was greatest in the first 6 months after cancer diagnosis, but continued to rise at 2 years. Figure 1C is a Kaplan–Meier plot of the incidence of VTE among those with NSCLC stratified by histology. Patients with adenocarcinoma had the highest incidence of VTE.

image

Figure 1.  Kaplan–Meier plots of the incidence of venous thromboembolism (VTE), after the diagnosis of non-small cell (A) and small cell lung cancer (B), respectively, stratified by stage and by histology for non-small cell lung cancer (C).

Download figure to PowerPoint

Figure 2A,D shows Kaplan–Meier survival plots comparing lung cancer cases that developed VTE within a year of diagnosis to a control sample of cases that never developed VTE, matching for survival from the cancer diagnosis date to the date of the VTE diagnosis, age (within 1 year), race, and initial cancer stage. Survival was measured from the VTE diagnosis date. Figure 2A,C shows Kaplan–Meier survival plots of the entire NSCLC cohort (Fig. 2A) stratified by initial localized or metastatic cancer stage (Fig. 2B,C). The development of VTE within a year of cancer diagnosis was associated with decreased survival among all cases of NSCLC, with the greatest differences being observed among localized and regional stage disease (data for regional stage disease not shown). A similar Kaplan–Meier survival plot for SCLC is shown in Fig. 2D, with a decreased effect of VTE on survival as compared to NSCLC. Among lung cancer patients who developed VTE and the matched controls who did not develop VTE, the causes of death listed on the death certificates were analyzed. Of the 572 lung cancer patients who developed VTE and died, the three most common causes of death were lung cancer (75%), chronic ischemic heart disease (2%), and PE (2%). Among 1193 matched controls that did not develop VTE, the three most common causes of death were lung cancer (79%), chronic ischemic heart disease (2%), and chronic obstructive pulmonary disease (1%).

image

Figure 2.  Kaplan–Meier plots of the incidence of death after the venous thromboembolism (VTE) diagnosis date and in a matched cohort without VTE, among the entire non-small cell lung cancer cohort (A) and in localized (B) and metastatic (C) stage non-small cell cancer, and among the entire small cell lung cancer cohort (D). Control and VTE cases were matched on survival from the cancer diagnosis date to the VTE diagnosis date, and survival was measured from this date.

Download figure to PowerPoint

Table 4 shows the results of a multivariate analysis of potential risk factors associated with death within 2 years of NSCLC or SCLC diagnosis. Significant factors among all lung cancers included advancing age, number of comorbidities, cancer stage, and the development of VTE. Patients who developed VTE after NSCLC and SCLC were 2.3 and 1.5 times more likely to die (< 0.0001), respectively, than those without VTE. Women with lung cancer were significantly less likely to die than men. Among those with NSCLC, Asians were less likely to die than Caucasians [hazard ratio (HR) 0.8, 95% CI 0.8–0.9]. In comparison to squamous cell histology, adenocarcinoma was associated with a modestly lower risk of death (HR = 0.91, 95% CI 0.89–0.93), whereas carcinoma NOS and large cell cancer were associated with higher risks (HR = 1.4, 95% CI 1.3–1.4, and HR = 1.1, 95% CI 1.1–1.2, respectively).

Table 4.   Effect of sex, age, race, comorbidities, initial cancer stage, histology and venous thromboembolism on death within 2 years of lung cancer diagnosis
VariableNon-small cell lung cancerSmall cell lung cancer
Hazard ratio for death (95% CI)P-valueHazard ratio for death (95% CI)P-value
  1. CI, confidence interval. *Small cell lung cancer stages were limited (localized and regional) and extensive.

Sex (vs. male)0.87 (0.86–0.89)<0.00010.9 (0.8–0.9)<0.0001
Age (vs. <45 years)
 45–64 years1.0 (1.0–1.1)0.21.1 (0.9–1.2)0.31
 65–74 years1.2 (1.1–1.3)<0.00011.3 (1.2–1.5)<0.0001
 > 75 years1.6 (1.5–1.7)<0.00011.9 (1.7–2.2)<0.0001
Race (vs. Caucasian)
 Black1.0 (0.9–1.0)0.11.0 (0.9–1.0)0.36
 Hispanic1.0 (0.97–1.0)0.91.1 (1.0–1.1)0.09
 Asian American0.8 (0.8–0.9)<0.00010.9 (0.8–0.9)0.002
Number of chronic comorbid conditions (vs. 0)
 11.20 (1.17–1.22)<0.00011.3 (1.3–1.4)<0.0001
 21.31 (1.28–1.34)<0.00011.5 (1.4–1.5)<0.0001
 31.6 (1.6–1.7)<0.00011.9 (1.8–1.9)<0.0001
SEER stage (vs. localized)
 Regional2.0 (2.0–2.1)<0.0001  
 Metastatic5.2 (5.1–5.4)<0.00012.3 (2.2–2.4)<0.0001
Histological subtype (vs. squamous cell carcinoma)
 Adenocarcinoma0.91 (0.89–0.93)<0.0001  
 Large cell carcinoma 1.1 (1.1–1.2)<0.0001  
 Carcinoma NOS1.4 (1.3–1.4)<0.0001  
Venous thromboembolism2.3 (2.2–2.4)<0.00011.5 (1.3–1.7)<0.0001

Discussion

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflict of Interests
  9. References

A major finding of this study was that the 1-year cumulative incidence of VTE was high, at 3%, a figure consistent with the findings of recent cohort studies [3,19]. The current study further analyzed the incidence of VTE among those with NSCLC and SCLC histology, and found that the highest incidence occurred within 6 months of cancer diagnosis, averaging 7.2 VTE events/100 patient-years.

Interestingly, the incidence of VTE in those with NSCLC was highest in those patients younger than 45 years, and this finding remained significant in a multivariate analysis that adjusted for initial cancer stage, number of comorbidities, and histology. Although the lung cancer literature does not support age alone as an independent prognostic factor [20–22], possible explanations for this finding include a biologically more aggressive cancer in younger patients, increased use of chemotherapy, and/or increased thromboprophylaxis in older patients. Furthermore, adenocarcinoma histology was twice as likely to be associated with the development of VTE than squamous cell carcinoma. This finding is consistent with clinical practice and published reports [10–12]. Mucin-producing adenocarcinomas of the lung and other sites have been associated with increased risk of VTE, suggesting that the presence of mucin may result in increased procoagulant secretion [23]. Additionally, there is evidence to suggest that mucins activate platelets and microthrombi in microvasculature [12].

The second major finding was that the development of VTE was associated with decreased survival among patients with NSCLC and SCLC, even after adjustment for other risk factors associated with death. As noted in patients with breast, colon and ovarian cancer [24–26], this effect was greatest among cases initially diagnosed with local or regional stage disease. In an analysis of the cause of death, nearly 80% were attributed to lung cancer, both among those who developed VTE and in matched controls. Only 2% of patients who developed VTE died as a result of the thromboembolism. These findings support VTE as a marker for recurrent or advanced cancer or for a more biologically aggressive tumor.

Lacking any treatment data, it is unknown if and how these lung cancer patients with VTE were treated with anticoagulants. If decreased survival among patients with VTE is a reflection of tumor biology, survival may be potentially improved by anticoagulation and disruption of the procoagulant pathway [27]. Anticoagulants also have alleged antiangiogenic effects, which is particularly interesting given that the addition of bevacizumab, the monoclonal antibody targeting the vascular endothelial growth factor, to chemotherapy improved survival in those with advanced NSCLC [28]. Studies in SCLC with this agent are ongoing. Although these results are intriguing, prior clinical trials of anticoagulation in addition to chemotherapy in SCLC have yielded conflicting results. Some trials suggested improvement in survival and disease progression [6,8,9], although the type of anticoagulation, the therapeutic goal and treatment duration varied among these studies. The largest trial failed to demonstrate a survival advantage in those with SCLC given warfarin in addition to chemotherapy, and there were more warfarin-related deaths [7]. Thus, the role of anticoagulation in lung cancer remains unclear.

In this study, females with NSCLC and SCLC had a significantly lower likelihood of dying than males, a finding supported by prior clinical trials [29,30] and the SEER database (http://seer.cancer.gov).

In patients with NSCLC, advanced disease was the strongest independent predictor of VTE [3–5], with a 4-fold higher risk of VTE in patients who presented with metastatic NSCLC than in those with localized disease. This has been a consistent finding among common cancers [5]. The number of chronic comorbid conditions was also a strong predictor of VTE among NSCLC and SCLC patients. An increasing number of chronic comorbid conditions has been associated with a higher incidence of VTE in the general population [31,32], and this appears to be true among lung cancer cases. In patients with SCLC, the only significant predictor of VTE was the number of chronic comorbid medical conditions. This finding may reflect increased biological aggressiveness that is independent of other factors.

Interestingly, the risk for VTE was significantly lower among patients eligible for lung cancer-related surgery. This lower risk was also observed in patients undergoing surgery for colorectal and breast cancer [24,25]. A small study previously reported an increased incidence of VTE in lung cancer patients who underwent more extensive surgery [11]. However, our findings probably reflect the selection of lower-risk individuals who have early-stage disease and less comorbidity. In addition, the use of thromboprophylaxis may lower the incidence of perioperative VTE, but this information is not in the database. Even with surgically resectable disease, the development of thromboembolism after pneumonectomy has been associated with a lower than expected survival at 18 months, despite censoring for VTE-related deaths [33].

Despite the large cancer cohort and robust database, there are limitations to this study. These include the lack of information on specific cancer-related or anticoagulant treatment during the study period. Although a prior cohort study abstracted for treatment effects, continuation or change of treatments could not be confirmed [12]. The hospital database records extensive admission-related diagnoses and procedure codes, but does not collect patient information on other factors that may increase the risk for VTE, including individual body mass index and immobility. In addition, the SEER staging used by the Cancer Registry does not distinguish between operable and non-operable regional stage NSCLC, which are associated with different clinical outcomes. Finally, the database did not have any information regarding the use of primary thromboprophylaxis; however, this was not common practice during the study period [34,35].

In summary, this large population-based cohort study of NSCLC and SCLC confirmed a 3% incidence of VTE in the first year after cancer diagnosis. The development of VTE was associated with decreased survival and may reflect the biological aggressiveness of the malignancy. Investigators are utilizing surrogate blood markers [36] and genomic approaches [37] to identify lung cancer patients at greatest risk of VTE. Because low molecular weight heparin is superior to warfarin in preventing recurrent VTE in cancer patients [38,39], consideration should be given to larger clinical trials of low molecular weight heparin in those with NSCLC and SCLC to validate these observations.

Acknowledgement

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflict of Interests
  9. References

This study was funded in part by a National Institutes of Health grant (1-RO3- CA99527-01) to H. K. Chew.

Disclosure of Conflict of Interests

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflict of Interests
  9. References

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflict of Interests
  9. References
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