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Screening for Occult Cancer in Patients with Venous Thromboembolism
Jodi L. Grabinski, Pharm.D.*
July, 2004
The incidence of new cancers in patients diagnosed with idiopathic venous thromboembolism (VTE) is approximately 4-10%.1 Retrospective and prospective studies evaluating the benefit of screening for occult malignancy in patients diagnosed with VTE demonstrate that when cancer is detected it is generally identified at an earlier stage. There are data in a number of different cancers suggesting that early detection reduces mortality. However, there are no studies to date demonstrating that screening for malignancy in patients with VTE reduces mortality. Two recent studies published in the Journal of Thrombosis and Haemostasis address the issue of screening for occult cancer in patients diagnosed with VTE.
The first study by Monreal and colleagues2, was a prospective cohort follow-up study in which the primary goal was to assess the sensitivity of diagnostic work-up for occult malignancy in patients with VTE. A total of 864 patients were eligible for routine clinical evaluation. This evaluation included screening for malignancies by medical history, physical exam (included pelvic, rectal, and breast exams), laboratory tests, or chest X-ray. Cancer was diagnosed in 34 patients (3.9%) which translates into a sensitivity of identifying malignancy by routine examination of 55.7% (95% CI, 43.3-67.5%). Further limited diagnostic work-up was conducted in those who were not diagnosed with malignancy by routine clinical evaluation. This work-up included measurements of cancer markers (PSA, CA125) and abdomino-pelvic ultrasonography and identified malignancies in 13 additional patients for a sensitivity of 48.1% (95% CI, 30.7-66.0%). Approximately 60% of cancers diagnosed by the limited diagnostic work-up were defined as early stage cancers. Logistic regression analysis indicated an association with age >70 years and idiopathic thromboembolism as risk factors for occult malignancies.
The randomized multicenter clinical trial conducted by Piccioli and colleagues3, was designed to compare extensive screening for occult malignancy with no screening in patients with acute idiopathic VTE. The primary outcome evaluated cancer related mortality and the secondary outcome evaluated the cluster of cancer-related mortality, documented residual malignancy, or recurrent malignancy at 24 months. Based on sample size calculation, 500 patients per group would be required to detect a 75% reduction in cancer related mortality. The study had accrued a total of 201 patients (99 extensive screening, 102 control group) at the time it was terminated. The low accrual rate was thought to be a result of the Zelen randomization procedure and the tendency to screen patients in the control group. Cancer related mortality occurred in 2% of the extensive screening group compared to 3.9% in the control group, an absolute difference of 1.9% (95% CI, -5.5-10.9%). The secondary outcome event occurred in 5.1% of the patients in the extensive screening group versus 7.9% of the control patients, an absolute difference of 2.8% (95% CI, -6.3-13.4%).
The results of these studies again raise the question of should we be screening all patients with VTE for occult malignancy? One major question that needs to be answered is whether or not screening provides a survival advantage. Although the study by Piccioli et al. attempted to answer this question, the early termination of the study led to an insufficient number of patients to provide a definitive answer. It is difficult to predict if they had achieved their sample size goal if the results may have achieved statistical significance. Secondly, is it cost effective to screen all patients diagnosed with VTE and how extensive a work-up should be conducted at the time of diagnosis? It may not be cost effective to screen all patients at diagnosis, but identifying certain characteristics that are associated with the risk of malignancy may reduce costs. Previous studies have identified younger age to have a higher association of VTE and cancer, however Monreal et al. identified age >70 years and idiopathic VTE as risk factors for occult cancer. Screening patients >70 years old may not provide as great a survival advantage compared to younger patients. For example, prostate cancer was the most common type of cancer diagnosed in two previous cohort studies.4,5 The American Cancer Society (ACS) Screening Guidelines recommend a PSA test and digital rectal examination in men with a life expectancy of at least 10 years. Therefore, screening for prostate cancer in older patients is not indicated according to the ACS screening guidelines. Placing our efforts into screening younger patients with idiopathic VTE may provide greater survival advantage. The extent of the diagnostic work-up in these patients should include at least a routine examination and should be performed in accordance with current screening recommendations. Although the question of whether increased survival is achieved by screening remains unknown, the known association between VTE and occult cancer support work-up for malignancy.
References
1. Otten H-M, Prins MH. Venous Thromboembolism and Occult Malignancy. Thromb Res. 2001;102(6):V187-194.
2. Monreal M, Lensing AWA, Prins MH, Bonet M, Fernandez-Llamazares J, et al. Screening for occult cancer in patients with acute deep vein thrombosis or pulmonary embolism. J Thromb Haemost. 2004;2:876-881.
3. Piccioli A, Lensing AWA, Prins MH, Falanga A, Scannapieco GL, et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost. 2004;2:884-9.
4. Monreal M, Fernandez-Llamazares J, Perandreu J, Urrutia A, Sahuquillo JC, Contel E. Occult cancer in patients with venous thromboembolism: which patients, which cancers. Thromb Haemost. 1997;78:1316-8.
5. Rajan R, Levine M, Gent M, Hirsh J, Geerts W, et al. The occurrence of subsequent malignancy in patients presenting with deep vein thrombosis: results from a historical cohort study. Thromb Haemost. 1998;79:19-22.
*Dr. Grabinski, who is a guest editor, is Pharmacogenomics Fellow in the Division of Pharmacotherapy at the University of Texas Health Science Center at San Antonio.
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