Deep-vein thrombosis and the incidence of subsequent symptomatic cancer Reported by: Prandoni P et al. N Engl J Med. 1992;327:1128-1133.
Methods: The study enrolled 260 consecutive patients with confirmed DVT, 250 of whom were followed for 2 years. The incidence of a subsequent diagnosis of cancer in the 105 patients with secondary venous thromboembolism (VTE) was compared with the incidence of cancer in 145 patients with idiopathic VTE. Results: Cancer was identified in 5 of 153 patients (3.3%) and 0 of 107 patients, with idiopathic and secondary VTE, respectively, at the time of VTE diagnosis. Cancer developed in 2 of the 105 (1.9%) patients with secondary VTE during follow up and in 11 of the 145 (7.6%) patients with idiopathic VTE (odds ratio 2.3; P=.043). Thirty-five of the 145 idiopathic VTE patients had recurrent DVT, of which 6 (17.1%) were subsequently diagnosed with cancer. Cancer incidence rates were higher in patients with idiopathic VTE compared with those with secondary VTE (odds ratio 9.8; P=.008). Conclusions: The association between idiopathic VTE and the subsequent development of cancer is statistically significant and clinically important. This association is particularly strong among patients in whom VTE recurs during follow up.
INTRODUCTION ! Multiple studies have demonstrated that the incidence of VTE is considerably higher in patients with malignancies than in patients with nonmalignant diseases; however, the link between idiopathic VTE and subsequent risk for cancer is less clear ! This prospective, cohort study examined whether there is an association between VTE and risk for subsequent clinically overt cancer. METHODS ! All consecutive outpatients with venographically proven DVT, admitted to the Second Department of Internal Medicine of the University of Padua, were eligible for the study. Patients with recurrent VTE or known cancer were excluded !
Patients with a first episode of idiopathic or secondary DVT and no signs of cancer were assessed and followed for 2 years ! Secondary VTE was defined as VTE in patients with a family history of VTE, patients who had a lupus anticoagulant, or who were deficient in antithrombin III, protein C or protein S, and patients with trauma to a lower limb ! All other cases of VTE were defined as idiopathic ! A limited search for cancer was conducted at the time of the referral ! All patients were treated with continuous adjusted-dose IV heparin or fixed-dose subcutaneous low-molecular-weight heparin (LMWH), followed by warfarin after 7 days of treatment
!
Patients with recurrent VTE were reevaluated for cancer
!
The incidence of cancer in patients with idiopathic DVT was compared with patients with secondary DVT; the incidence of cancer was also compared in patients with single and recurrent episodes of VTE
RESULTS Patients ! Of the 250 patients who continued through the duration of the followup analysis, 105 (42%) and 145 (58%) had secondary and idiopathic VTE, respectively; clinical characteristics are summarized in Table 1
Table 1. Characteristics of the follow-up patients at study entry Characteristic Mean (±SD) age – yr Sex – no. Male Female Tobacco use – no. (%) Alcohol abuse – no. (%) Estrogen use – no. (%) Liver disease – no. (%)
Idiopathic DVT (N=145) 62.9 ± 14.3
COPD – no. (%)*
!
Secondary DVT (N=105) 55.1 ± 18.7
87 58 51 (35) 5 (3.4) 3 (2.1) 4 (2.8)
55 50 29 (28) 6 (5.7) 9 (8.6) 4 (3.8)
12 (8.3)
7 (6.7)
The cumulative incidence of cancer in patients secondary VTE, idiopathic VTE, or recurrent idiopathic VTE is summarized in Figure 1 ! The difference between the incidence of cancer in patients with secondary VTE and those with idiopathic thrombosis was statistically significant (odds ratio, 2.3; P=.043) ! The incidence of cancer was significantly higher in patients with recurrent idiopathic VTE compared with patients with secondary VTE (P=.008) and patients with non-recurrent idiopathic VTE (P=.024)
*COPD=chronic obstructive pulmonary disease
!
!
CONCLUSIONS ! The incidence of clinically overt cancer following idiopathic DVT was statistically significant and clinically important ! For patients with recurrent idiopathic VTE throughout the 2 year follow-up period, the risk of cancer was even greater !
It is highly likely that malignancies which became clinically apparent within 1 year of DVT diagnosis may have been present but asymptomatic at the time of DVT diagnosis
!
For patients with secondary DVT, risk of cancer remained low
Figure 1. Cumulative incidence of cancer in patients with secondary thrombosis, idiopathic thrombosis, and recurrent idiopathic thrombosis 30
Secondary VTE ! During a mean 82.6 weeks of follow up, 5 (4.8%) of the 105 patients with secondary VTE died of nonmalignant disease and 2 were lost to follow up (Table 2) ! Two patients with secondary VTE had cancers diagnosed after 11 and 18 months, respectively; both were aged ≥60 years ! Five patients with secondary VTE had recurrent VTE; none developed cancer
Cumulative incidence (%)
ABSTRACT Background: While there is an established relation between cancer and subsequent diagnosis of deep vein thrombosis (DVT), the relation between DVT and a subsequent diagnosis of cancer is unclear. This prospective cohort study examined the incidence of clinically overt cancer in patients with a previous diagnosis of DVT.
Idiopathic VTE ! During a mean of 79.8 weeks, 13 (9%) of 145 patients with idiopathic VTE died of nonmalignant disease (Table 2) ! Cancer developed in 11 (7.6%) of patients with idiopathic VTE; 6 of these cases occurred in patients aged ≥60 years ! Recurrent VTE was observed in 35 (24.1%) patients; 6 of the 11 patients with idiopathic VTE in whom cancer later developed had recurrent VTE
Recurrent idiopathic thrombosis (n=35)
20
10
All idiopathic thrombosis (n=145)
Secondary thrombosis )n=105)
0
26
52
78
104
Weeks
! Table 2. Incidence of cancer during follow up in patients with secondary of idiopathic venous thrombosis Variable 0-6 Secondary thrombosis (n=105) Incidence of cancer (no./no. at risk) Death from nonmalignant causes (no.) Lost to follow-up (no.) Idiopathic thrombosis (n=145) Incidence of cancer (no./no. at risk) Death from nonmalignant causes (no.) Lost to follow-up (no.)
0/105
Months of Follow Up 7-12 13-18 19-24
1/93
1.82
0/72
Total
2/105
3
1
1
0
5
0
1
1
0
2
6/145
3/121
2/108
0/97
11/145
7
5
0
1
13
0
1
0
0
1
*The incidence of cancer in the patients with idiopathic DVT was significantly higher than that in the patients with secondary thrombosis in the first 6 months of follow up (P=.048) and the total period (P=.043)
Characteristics of patients with cancer are shown in Table 3
Table 3. Characteristics of the patients with cancer and results of diagnostic testing Patient No.
Sex/Age
Histologic Diagnoses
Idiopathic Thrombosis (first episode) 1 M/58 Leiomyosarcoma 2 F/59 Glioblastoma of brain 3 M/63 Adenocarcinoma of colon 4 M/75 Adenocarcinoma of pancreas 5
F/58
Adenocarcinoma of breast
Recurrent Idiopathic Thrombosis 6 M/73 Adenocarcinoma of pancreas 7 F/49 Cystadeno-carcinoma of ovary 8 M/54 Adenocarcinoma of lung 9 M/65 Adenocarcinoma of prostate 10 M/84 Glioblastoma of brain 11 F/72 Adenocarcinoma of stomach Secondary Thrombosis 12 F/76 Adenocarcinoma of uterus 13 M/74 Adenocarcinoma of prostate
Cancer Stage
Time Between Diagnosis or Thrombosis and Diagnosis of Cancer* wk
Clinical Manifestations leading to Diagnosis of Cancer
Additional Diagnostic Tests Performed When Cancer Suspected
T1N0M0 T4N4M1 T4N2M1
8 8 21 21
Local pain, tumor Naurologic deficits Jaundice, weight loss Jaundice, anorexia, weight loss Breast node
Surgical biopsy CT scan Colonoscopy, biopsy CT scan, surgical biopsy
T1N1M0
73
T4N1M1 T1N0M0
13 (5) 24 (7)
Jaundice Pelvic pain
CT scan, biopsy Laparoscopic biopsy
T1N1M0
30 (13)
Bronchoscopy, biopsy
T3N1M1 T2N2M0
48 (5) 48 (4) 78 (34)
Coughing, weight loss, hemoptysis Lumbar back pain Neurologic deficits Abdominal pain, weight loss
Bone scan, biopsy CT scan Gastroscopy, biopsy
T1N0M0 T2N0M0
47 78
Postmenopausal blood loss Prostatism
Colposcopic biopsy Ultrasonography, biopsy
Mammography, surgical biopsy
For educational purposes only. These were not prepared or reviewed by the primary author.