Cancer is associated with a prothrombotic state and VTE can be the first manifestation of an occult cancer. However, previous studies failed to show an advantage of extensive cancer screening in patients with VTE, especially unprovoked, to detect hidden cancers in terms of improved survival, cancer-related morbidity, or quality of life, despite an earlier cancer diagnosis [5, 11]. An individual patient data meta-analysis of 1830 subjects with unprovoked VTE enrolled in clinical trials on limited versus extensive screening for occult malignancy found that extensive screening was not effective in reducing overall mortality [12].
The measurement of biomarkers for both cancer and thrombosis, such as DD could help identify those patients with VTE who would benefit of a more extensive evaluation for cancer [33]. Previous studies analyzed the association between DD levels at VTE presentation and the presence of overt or hidden cancer. Cushman et al. [19] showed that high DD levels were not associated with cancer related thrombosis in two prospective observational studies; however, patients were asymptomatic without DVT at baseline. Rege et al. [20] showed a negative association between low level DD (< 1,000 ng/mL) and development of malignancy at 12 months in a sample of only 100 patients with DVT. In a post-hoc analysis of a diagnostic management study in 218 outpatients with both provoked and unprovoked acute DVT, with a median follow-up of 34 months, Schutgens et al. [21] found a cancer prevalence of 32% in the group with DD greater than 4,000 ng/mL and of 16% in patients with lower DD levels (p = 0.009, relative risk = 2.0), in particular in patients with unprovoked DVT. However, the majority of enrolled patients had known cancer (n = 28) and only a limited number of newly diagnosed cancers were detected at presentation (n = 8) and follow- up (n = 14). Paneesha et al. [22] reported an increased incidence of malignancy with DD above 8,000 ng/mL at presentation (50%) compared with those with lower levels (13.3%) in 699 subjects with DVT and PE over a follow-up of 23.2 months. However, the authors did not provide any details about either provoked and unprovoked VTE and 188 patients (25.4%) had known malignancy. Prognostic factors for occult cancer were age > 60 years, and thrombosis above the knee. Han et al. [23] also found that, in 169 patients with unprovoked VTE, DD levels above 4,000 ng/mL were independently associated with occult metastatic cancer over a follow-up of 5.3 years compared with DD below 2,000 ng/mL, after adjusting for age, sex and type of VTE. However, 21 cancers were detected during hospitalization for VTE and only three during the follow-up. In addition, Gran et al. [24] showed that D-dimer > 5000 ng/ml at incident VTE was associated with a higher risk of subsequent cancer within one and two years in 422 patients with symptomatic VTE events in any site of the Tromsø 1–6 surveys from 1994 to 2012. Felix et al. [25] also reported that patients with D-dimer > 15 µg/mL presented a > 2-fold higher risk of being diagnosed with a cancer condition in the upcoming 2 years in a retrospective cohort of 562 patients with acute pulmonary embolism. However, in this study a known active cancer was present in 126 (22.4%) patients. More recently, the REMOTEV registry showed that cancer developing after VTE diagnosis was associated only with age over 65 years and the concomitant presence of an unusual site and lower-limb deep vein thrombosis in a cohort of 993 patients. They had both provoked and unprovoked VTE and developed 58 cancers within a year of follow-up. However, DD at VTE diagnosis was not found to be associated with occult cancer [26].
In our cohort, we chose to exclude VTE patients with known overt cancer at the time of VTE index event and to consider that DD could be a marker of hidden cancer, becoming overt within one year after VTE diagnosis. We also chose to include patients with both provoked VTE and calf DVT.
DD levels at VTE diagnosis appeared significantly higher in patients who developed overt cancer within a year (median 3,550 versus 2,700 ng/mL P = 0.01). In particular, patients who developed cancer during follow-up had a higher frequency of higher DD, either above the highest quartile of our cohort (> 5,710 ng/ml) when compared with cancer-free patients. Similar results were observed when DD cut-offs of 4,000 ng/mL or 8,000 ng/mL were considered, as proposed by previous studies. Our data are in line with those study previously exploring DD predictive value for hidden cancer [21–25], although with different cut-offs ,variable length of follow-up and varying proportions of patients with overt cancer at VTE diagnosis. .
A multivariate regression analysis of our data showed that age above 60 years and DD above 8,000 ng/mL were independently associated to the development of overt cancer during follow-up, with no significant interaction between age and DD, and DD and VTE extension. A similar proportion of subjects with either cancer or cancer-free had provoked VTE. We also did not find an effect of previous VTE or previous cancer.
Based on these observations, patients older than 60 years could take advantage of a more extensive screening for cancer, especially those with high DD levels (above 8,000 ng/mL) at VTE diagnosis.
In our population the cumulative incidence of newly diagnosed malignancy within a year was low (4.6 per 100 patient-years; 95% CI 3.3–6.3) and in keeping with data from the literature [5, 11, 21–25]. Twelve cancers (32%) were detected during the initial work-up and we found a similar rate of provoked VTE in cancer-free patients and in those who developed a malignancy. Even if the risk of harboring an occult cancer is higher in unprovoked VTE, if compared to general population [7], current guidelines do not suggest extensive cancer screening [33].
There is still debate on the most appropriate diagnostic tests for cancer screening in VTE patients, especially if unprovoked. Randomized clinical trials comparing extensive screening (including total body CT scan, endoscopy) with standard work-up revealed a very high sensitivity of the extensive screening (93%) but failed to demonstrate a net clinical benefit [2, 11]. Monreal et al. [13] performed a prospective cohort follow-up study where all the patients negative at initial examinations underwent a limited work up (comprehensive of abdominal-pelvic ultrasound and markers for cancer measurement) which identified 13 of 27 malignancies which became symptomatic after 1 year of follow up (sensitivity of 48.1%). Van Doormaal et al. [9] showed the extremely low yield of abdominal and chest CT scan (plus mammography in women) as screening procedure (sensitivity was 33% and the cancer related mortality was higher in the extensive screening group). Other studies investigated the role of 18F-fluorodesoxyglucose positron-emission tomography/computed tomography (FDG-PET/CT) with contrasting results. In the pilot study by Rondina et al. [10] forty patients underwent FDG-PET/CT examinations, and 25/40 (62.5%) had abnormal results but only 1/40 was diagnosed with cancer (of notice, it was a symptomatic and extended pancreatic mass that could probably have been detected by abdomen ultrasounds). In the study by Alfonso et al. [34], 31.3% (31/99) patients tested had abnormal FDG-PET/CT results and additional diagnostic work up confirmed diagnosis in 7/31, two more were diagnosed with cancer during 2-year follow up (sensitivity 77.8%). Robin et al. [12] found that a strategy including limited screening (physical examination, usual laboratory tests, and basic radiographs) and FDG-PET/CT was not associated with a significantly higher rate of cancer diagnosis after unprovoked VTE in comparison with the limited screening only. In an open-label, multicenter, randomized study in four French university hospitals, a strategy including limited screening and a FDG PET/CT was not associated with a significantly higher rate of cancer diagnosis after unprovoked VTE than limited screening alone [35]. However, the risk of subsequent cancer diagnosis was lower in patients who had negative initial screening that included FDG PET/CT than in patients who had negative initial limited screening. More recently, an individual patient data meta-analysis, including prospective studies assessing cancer screening in patients with unprovoked VTE, showed that FDG-PET/CT has satisfactory accuracy indices for cancer diagnosis in patients with unprovoked VTE [36]. In particular, it exhibited a very high negative predictive value and could rule out the presence of an underlying occult malignancy in this setting.
In our cohort 12 out of 37 cancer cases in VTE patients were identified at initial routine clinical examination giving a sensitivity of this procedure of 32%, while 12/25 (48%) of cancers diagnosed during follow-up were metastatic and they were not detected during the initial work-up.
Our experience thus confirms that a thorough physical examination, clinical history, routine laboratory tests (i.e. complete blood count, liver and renal function, urinalysis, protein electrophoresis, lactate dehydrogenase, PSA in men, occult fecal blood test and PAP-test as indicated for screening in the general population) mammography and chest X-ray have a low sensitivity in detecting cancers that will be symptomatic in a year follow-up. In patients with DD above 8,000 ng/mL at VTE diagnosis, an additional evaluation based on abdominal-pelvic ultrasound or CT scan and endoscopy could be reasonable, given the fact that the most frequent cancer associated with VTE are gastrointestinal, liver, lung, ovary and pancreas [8].
The multivariable analysis showed that DD level as a continuous variable was not an independent risk factors of cancer development after VTE diagnosis. This might imply that D-dimer was not necessarily a strong risk factor. Considering the quite high odds ratio of age > 60 years (multivariate HR: 11.77), old age could be a quite important factor, and the influence of D-dimer level could be relatively low.
Limitations of our study are its retrospective design, the limited number of cancers detected after VTE diagnosis, and the lack of data regarding the duration of symptoms before VTE diagnosis as this could also influence DD levels at VTE diagnosis. Other variables, which were described in previous reports, including current smoking, chronic lung disease, anemia, elevated platelet count and could influence DD levels, were not available. The study period (2008–2018) might be relatively long and a different time period could be associated with different management strategies.
Strengths are the inclusion of patients without overt cancer at VTE diagnosis, as this allows a better assessment of the association between DD and subsequent overt cancers, and the 12-month follow-up, as it is more plausible that DD at VTE diagnosis can be associated with cancer developing in a short time frame.
Our data confirm that the frequency of hidden cancer is low in patients with VTE and it shows that patients older than 60 years may deserve extensive cancer screening, while DD may not be a strong risk factor although DD above 8,000 ng/mL might be an index to occult cancer. Further studies are required to assess the role of DD in identifying VTE patients who may benefit from cancer screening and to set more efficient screening programs [37].
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