Abstract
Background
Venous thromboembolism (VTE) is a frequent complication in patients with cancer and causes considerable morbidity and mortality. The risk of VTE is higher in patients with pancreatic cancer and is often associated with treatment delays or interruptions. Recently, the ONKOTEV score was proposed as a VTE risk predictor model for patients with cancer, but its validation is still ongoing.
Patients and Methods
We conducted a retrospective study to determine the incidence of VTE and to evaluate the ONKOTEV score as a VTE predictive tool in a population of patients with pancreatic cancer.
Results
Between February 2012 and May 2017, 165 patients were included in the study. The median age was 73 years, 45.5% of patients were female, and 55.8% had stage IV disease. Fifty‐one patients had a VTE (30.9%); 23.5% had pulmonary embolism, 25.5% had deep venous thrombosis, and 51.0% had visceral VTE (VsT). At a median follow‐up time of 6.3 months, cumulative incidence of VTE was less than 10% for ONKOTEV scores 0 or 1 and approximately 40% and 70% for scores 2 and ≥3, respectively.
Conclusion
The high VTE incidence observed in this study is consistent with prior reports. Patients at high risk for VTE with no increase in hemorrhagic risk should be considered for primary thromboprophylaxis. The ONKOTEV score may stratify VTE risk in patients with pancreatic cancer, with ONKOTEV score ≥2 being associated with a higher VTE occurrence.
Implications for Practice
Venous thromboembolism (VTE) is a frequent complication of patients with pancreatic cancer and causes considerable morbidity, treatment delays or interruptions, and mortality. Thromboprophylaxis is not used routinely in ambulatory patients. Tools to stratify the risk of VTE are important to help select patients who may benefit from thromboprophylaxis. Recently, the ONKOTEV score was proposed as a VTE risk predictor model for patients with cancer, but its validation is still ongoing. In this patient series, ONKOTEV score ≥2 was associated with high VTE occurrence and may stratify VTE risk in patients with pancreatic cancer, suggesting that ONKOTEV can be considered to select patients with pancreatic cancer for primary thromboprophylaxis.
Keywords: Venous thromboembolism, Pancreatic cancer, Risk prediction, ONKOTEV
Short abstract
Venous thromboembolism is a common complication of pancreatic cancer. This retrospective study was conducted to determine the incidence of VTE and to evaluate the ONKOTEV score as a VTE predictive tool in a pancreatic cancer population.
Introduction
Venous thromboembolism (VTE) is an important cause of morbidity and mortality, being the second leading cause of death in patients with cancer 1. VTE can lead to treatment delays or interruptions and is associated to higher health care resource utilization and costs 2. Cancer type, stage, chemotherapy regimen, obesity, previous history of VTE, and other factors influence the individual risk of venous thrombosis 3, 4.
Pancreatic cancer is one of the malignancies more associated with VTE 4, 5, 6. This high risk is mediated by pancreatic cancer cells, which activate platelets and procoagulant factors, such as tissue factor and thrombin 7.
Hospitalized patients with cancer have a high incidence of VTE; therefore, prophylactic anticoagulation therapy with low‐molecular‐weight heparin (LMWH) is recommended in the absence of bleeding or other contraindication 8, 9, 10. After major cancer abdominal or pelvic surgery, anticoagulant thromboprophylaxis with LMWH for approximately 1 month, after hospital discharge, is also recommended 8. Ambulatory patients have varying VTE risk because of several factors, and although thromboprophylaxis is not routinely used in this setting, VTE prevention can be considered for high‐risk outpatients receiving chemotherapy 10, 11.
Recently, the ONKOTEV score was proposed as a VTE risk model for patients with cancer, but its validation is still ongoing 12. The ONKOTEV score is based on four risk factors: presence of metastatic disease, compression of vascular/lymphatic structures, history of previous VTE, and Khorana score >2 12.
We conducted a retrospective study to evaluate the ONKOTEV score as a VTE predictive tool in a population of Portuguese patients with pancreatic cancer.
Materials and Methods
Design and Population
The present study is a retrospective single‐center observational analysis of all consecutive patients aged ≥18 years diagnosed with pancreatic carcinoma at Hospital Beatriz Ângelo, Portugal. Pancreatic neuroendocrine tumors were excluded.
The study protocol was approved by the Ethics Committee of Hospital Beatriz Ângelo. The requirement for written informed consent from study participants was waived because this is a retrospective study with anonymized patient data collection and analysis.
Data Collection
Data were collected by the authors from the hospital electronic medical records. Data collected included demographic variables, Eastern Cooperative Oncology Group performance status (ECOG PS); previous history of VTE; body mass index; date of pancreatic cancer diagnosis; disease stage; tumor location in the pancreas; vascular/lymphatic compression; surgery; chemotherapy regimen; platelet, neutrophil, and hemoglobin counts; chest and abdominal computed tomography (CT) scans; radiologic evidence of vascular invasion; lower limb doppler ultrasonography; date of VTE diagnosis; location; and treatment. Vascular/lymphatic compression and invasion was defined by CT scan throughout the oncologic disease. The ONKOTEV score was retrospectively calculated. A patient was considered lost to follow‐up if the last hospital visit was more than 4 months after the date of data collection.
Outcomes
The main objective of this study was to assess the ONKOTEV score as a VTE predictive tool in this population of patients with pancreatic cancer.
Statistical Analysis
All categorical variables were expressed as numbers or percentages. All continuous variables were expressed using median and interquartile range or mean and 95% confidence interval. Between‐group analysis was performed using the Mann‐Whitney U test or the χ2 test for continuous and discrete variables, respectively. Exploratory univariate logistic regression analyses were performed. Bonferroni's correction was applied when necessary. Tests were considered significant at α = .05 significance level (two‐sided). IBM SPSS version 20 was used for statistical analyses.
Results
Demographics and Tumor Characteristics
Between February 2012 and May 2017, 165 patients were diagnosed with pancreatic carcinoma. The median age was 73 years, 45.5% (n = 75) were female, and ECOG PS was ≤1 in 56.9% (n = 94) of the sample. More than half were classified as stage IV at diagnosis (55.8%). Liver was the most common site of metastasis (79.8%), followed by peritoneum (40.4%) and lung (20.2%). The main location of the primary tumor within the pancreas was head and uncinate process (61.8%). Forty patients (24.2%) underwent surgical resection, and 109 (66.1%) received chemotherapy at some point during the disease course. The ONKOTEV score was retrospectively determined, with 30 (18.2%), 63 (38.2%), 55 (33.3%), and 17 (10.3%) patients with an ONKOTEV score of 0, 1, 2, or ≥3, respectively. Of the four ONKOTEV risk factors, the most frequent was the presence of metastases (55.8%, n = 92), followed by vascular/lymphatic compression (40.6%, n = 67) and Khorana score >2 (35.8%, n = 59). Previous history of VTE was only present in seven patients (4.2%; Table 1). Three patients were lost to follow‐up after 3, 9, and 14 months of observation.
Table 1.
Patient demographics and tumor characteristics
| Variable | All (n = 165), n (%) | VTE (n = 51), n (%) | No VTE (n = 114), n (%) |
|---|---|---|---|
| Age, years, median (IQR) | 73.0 (13.0) | 72.0 (12.0) | 73.0 (13.0) |
| Gender: female | 75 (45.5) | 29 (56.9) | 46 (40.4) |
| ECOG PS at diagnosis | |||
| 0 | 39 (23.6) | 12 (23.5) | 27 (23.7) |
| 1 | 55 (33.3) | 17 (33.3) | 38 (33.3) |
| 2 | 37 (22.4) | 10 (19.6) | 27 (23.7) |
| 3 | 27 (16.4) | 9 (17.6) | 18 (15.8) |
| 4 | 7 (4.3) | 3 (5.9) | 4 (3.5) |
| Stage | |||
| I | 18 (10.9) | 2 (3.9) | 16 (14.0) |
| II | 23 (13.9) | 3 (5.9) | 20 (17.5) |
| III | 32 (19.4) | 6 (11.8) | 26 (22.8) |
| IV | 92 (55.8) | 40 (78.4) | 52 (45.6) |
| Location within the pancreas | |||
| Head/uncinate | 102 (61.8) | 26 (51.0) | 76 (66.7) |
| Body/tail | 63 (38.2) | 25 (49.0) | 38 (33.3) |
| Chemotherapya | |||
| Yes | 109 (66.1) | 35 (68.6) | 74 (64.9) |
| Gemcitabine‐based | 94 (56.9) | 29 (56.9) | 65 (57.0) |
| Platinum‐based | 35 (21.2) | 12 (23.5) | 23 (20.2) |
| Surgical resection: yes | 40 (24.2) | 7 (13.7) | 33 (28.9) |
| Radiologic vascular invasion: yes | 55 (33.3) | 27 (52.9) | 25 (21.9) |
| ONKOTEV score | |||
| 0 | 30 (18.2) | 1 (2.0) | 29 (25.4) |
| 1 | 63 (38.2) | 8 (15.7) | 55 (48.2) |
| 2 | 55 (33.3) | 28 (54.9) | 27 (23.7) |
| ≥3 | 17 (10.3) | 14 (27.4) | 3 (2.7) |
| Vascular/lymphatic compression: yes | 67 (40.6) | 36 (70.6) | 31 (27.2) |
| Presence of metastasis: yes | 92 (55.8) | 41 (80.4) | 51 (44.7) |
| Previous history of VTE: yes | 7 (4.2) | 7 (13.7) | 0 (0) |
| Khorana score | |||
| >2 | 59 (35.8) | 23 (45.1) | 36 (31.6) |
| 2 | 106 (64.2) | 28 (54.9) | 78 (68.4) |
Some patients were treated with more than one chemotherapy regimen.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, interquartile range; VTE, venous thromboembolism.
VTE Events
With a median follow‐up time of 6.3 months, 51 patients (30.9%) have been diagnosed with a VTE event. Of the 51 VTE events, 12 patients (23.5%) had pulmonary embolism (PE), 13 (25.5%) deep venous thrombosis (DVT), and 26 (51.0%) abdominal VTE, with splenic and portal veins being the most affected—11 (21.6%) and 9 (17.6%), respectively. Twenty‐six patients (51.0%) had a symptomatic VTE (Table 2). Three patients had both DVT and PE, all with symptomatic PE, and were classified as PE events. All but one symptomatic patient with an ECOG PS 4 and poor prognosis were treated with LMWH. Fifteen of the 26 symptomatic patients were treated as inpatients, with a median hospital stay of 10 days, with one death directly attributed to the VTE event (initial DVT with subsequent PE and death). Three patients with incidental VTE, two with PE and one with mesenteric vein thrombosis, were treated with anticoagulation. The incidence of VTE in the group of 40 patients who underwent surgical resection of the pancreatic tumor was 7 (4 with visceral VTE [VsT]) versus 44 (22 VsT) among the 125 patients who did not.
Table 2.
Characteristics of VTE events
| Variable | All VTE (n = 51), n (%) | Symptomatic VTE (n = 26), n (%) | Asymptomatic VTE (n = 25), n (%) |
|---|---|---|---|
| VTE location | |||
| Pulmonary embolism | 12 (23.5) | 9 (34.6) | 3 (12.0) |
| Lower limbs thrombosis | 13 (25.5) | 12 (46.2) | 1 (4.0) |
| Splenic vein thrombosis | 11 (21.6) | 0 (0.0) | 11 (44.0) |
| Portal vein thrombosis | 9 (17.6) | 4 (15.4) | 5 (20.0) |
| Other abdominal veins | 6 (11.8) | 1 (3.8) | 5 (20.0) |
| VTE requiring hospital admission | 15 (29.4) | 15 (57.7) | 0 (0.0) |
Abbreviation: VTE, venous thromboembolism.
VTE and ONKOTEV Score
At the time of diagnosis of pancreatic cancer, VTE was present in 20 patients; 10 patients (18.2%) and 8 patients (47.1%) with ONKOTEV scores of 2 and ≥3. For ONKOTEV scores of 0 and 1, one patient for each category had VTE at pancreatic cancer diagnosis: 3.3% and 1.6%, respectively. Over time, the cumulative incidence of VTE increased, particularly for ONKOTEV scores of 2 and ≥3. At the median follow‐up time of 6.3 months, VTE cumulative incidence was 41.8% and 70.6% for ONKOTEV scores 2 and ≥3, respectively, but less than 10% for patients with ONKOTEV 0 or 1. Cumulative incidence of VTE was 3.3%, 12.7%, 50.9%, and 82.4% for patients with ONKOTEV scores of 0, 1, 2, and ≥3, respectively (Fig. 1).
Figure 1.
Cumulative incidence of VTE by ONKOTEV score.Abbreviation: VTE, venous thromboembolism.
Survival Analysis and VTE Occurrence
There were no differences in the median overall survival between patients with VTE and patients without VTE: 5.6 versus 4.7 months (p = .530, log‐rank test; Fig. 2).
Figure 2.
Overall survival by presence or absence of VTE.Abbreviation: VTE, venous thromboembolism.
Predictors of VTE
On univariate logistic regression analyses, ONKOTEV ≥2, radiologic vascular invasion, vascular compression, and the presence of metastases were all risk factors for the occurrence of VTE. On the other hand, primary tumor located in head/uncinated process was a negative predictor of VTE occurrence (Table 3).
Table 3.
Univariate logistic regression analyses for predictors of VTE occurrence
| Predictors | VTE occurrence | ||
|---|---|---|---|
| B | Exp (B) (95% CI) | p value | |
| Vascular invasion | 1.388 | 4.005 (1.976–8.118) | <.001 |
| Tumor location (head/uncinate) | −0.732 | 0.481 (0.245–0.942) | .033 |
| Chemotherapy | 0.168 | 1.182 (0.584–2.394) | .642 |
| ONKOTEV: total score | |||
| 1 | 1.439 | 4.218 (0.503–35.388) | .185 |
| 2 | 3.404 | 30.074 (3.824–236.522) | .001 |
| ≥3 | 4.908 | 135.333 (12.889–1,420.950) | <.001 |
| ONKOTEV: vascular compression | 1.860 | 6.426 (3.096–13.335) | <.001 |
| ONKOTEV: metastization | 1.587 | 4.888 (2.233–10.700) | <.001 |
| ONKOTEV: previous VTE history | ND | ND (ND) | ND |
| ONKOTEV: Khorana score >2 | 0.576 | 1.780 (0.903–3.507) | .096 |
Abbreviations: B, unstandardized coefficient; Exp (B), exponential of B; CI, confidence interval; ND, not determined because the Hosmer‐Lemeshow test could not be computed; VTE, venous thromboembolism.
Discussion
The overall survival of patients with pancreatic carcinoma has not changed significantly in recent years, mostly for advanced disease, which has a poor prognosis 13, 14. Thus, it is critical to provide not only the best cancer treatment but also the best supportive care to maximize clinical benefit.
The association between thrombosis and pancreatic cancer was described many decades ago. In 1938, an autopsy study reported a 29.7% prevalence of thrombosis, rising to 56.2% when the malignancy was located in pancreatic body or tail 15, which is in accordance with our findings. Recent retrospective studies also reported VTE rates as high as 30% in patients with pancreatic carcinoma 16, 17.
Anticoagulation with LMWH for cancer‐related thrombosis and primary prophylaxis in hospitalized patients with cancer and after major surgery are recommended, with the main objective of decreasing VTE incidence, as long as no contraindications to anticoagulation use are present 8, 9, 10, 18. Because currently the majority of patients with cancer are treated as outpatients, the diagnosis of VTE events in the ambulatory setting will rise 19. However, primary prophylaxis in ambulatory patients is controversial and should be decided on a case‐by‐case basis, according to individual risk and with shared decision‐making with the patient. Thus, clinical tools to predict VTE risk are useful to establish the most appropriate cancer and supportive care treatments.
Recently, two multicenter randomized clinical trials, CASSINI and AVERT, evaluated the efficacy of rivaroxaban and apixaban administered for 180 days as thromboprophylaxis in ambulatory patients with cancer with an intermediate‐to‐high risk of VTE, defined by Khorana score ≥ 2, starting systemic chemotherapy 20, 21. The intervention period in these studies is similar to the median follow‐up of our series (6.3 months). CASSINI reported a nonsignificant decrease in incidence of VTE events of 2.8% (p = .100), and AVERT reported a significant decrease of 6% (p < .001), with an absolute increase of major bleeding (by International Society on Thrombosis and Hemostasis criteria) of 1% and 1.7% versus placebo, respectively. CASSINI included 274 (32.6%) patients with pancreatic cancer, with a reduction of VTE from 10.1% with placebo to 3.7% with thromboprophylaxis (p = .03) 22. This represents a number needed to treat of 16, with no increase in major bleeding events (2 vs. 3).
Several VTE risk prediction models have been proposed for outpatients with cancer, such as Khorana, Vienna Cancer and Thrombosis Study, PROTECHT, and CONKO scores, but, to date, the only validated model is the Khorana score, which was used in the CASSINI and AVERT studies 23, 24. Recently, the ONKOTEV score, which includes the Khorana score, presence of metastatic disease, compression of vascular/lymphatic structures, and history of previous VTE, was developed for ambulatory patients with cancer and showed a time‐dependent area under the curve significantly better than the Khorana score at both 3 months (71.9% vs. 57.9%, p = .001) and 6 months (75.4% vs. 58.6%, p < .001), but it is not yet validated 12, 25. Given the patients and tumor characteristics of our cohort we consider that it is representative of the overall population of patients with carcinoma of the pancreas diagnosed in Western populations 26, 27.
In our cohort, 51 of the 165 patients (30.9%) were diagnosed with a VTE event. The diagnosis of VTE was concomitant with the diagnosis of pancreatic carcinoma in 20 patients (12.1%), and, within a median follow‐up of 6.3 months, 31 further patients (18.8%) developed a VTE event. Approximately half (51.0%) of all VTE events were symptomatic, the majority (80.1%) with PE or DVT, and 57.0% of them were treated as inpatients for a median of 10 days, which illustrates the morbidity and health care cost of such a complication. Similar to other series, we did not document an impact of VTE on overall survival 2, 18, 28, 29. However, other authors have reported worse overall survival 30, 31, 32, 33.
With the advances of diagnostic imaging, VsT has become a well‐defined entity that is commonly diagnosed in patients with pancreatic cancer 34. VsT is undervalued when compared with PE or DVT, and, as a consequence, anticoagulation therapy, a safe therapeutic approach as long as bleeding risk is carefully assessed, is underutilized 34, 35. In our cohort VsT was asymptomatic in 21 of 26 patients and diagnosed by a CT scan, in the context of pancreatic cancer diagnosis, staging, or response evaluation. Only four patients with VsT, three of them symptomatic, received anticoagulation treatment, all with LMWH.
The incidence of VTE increased with increasing ONKOTEV score, with a cumulative VTE incidence of 3.3%, 12.7%, 50.9%, and 82.4% for ONKOTEV scores of 0, 1, 2, and ≥3, respectively (p < .001). These differences are sufficiently wide to support a useful predictive role for ONKOTEV score in patients with pancreatic cancer. There are no other studies validating the predictive impact of ONKOTEV, other than the original publication 12.
The distinction between radiologic tumor vascular compression and invasion is challenging, and both may be present in the same patient, because they represent a biologic continuum. Also, microscopic vascular infiltration is not possible to assess by radiology. Similar to the pivotal ONKTOEV trial, when tumor vascular encasement was present, the score for the variable vascular compression was zero (absent) 12. Radiologic vascular invasion is not considered in the ONKOTEV score, but our results suggest that when present it may be a risk factor for VTE.
Our study has several limitations. First, it is a retrospective study with all its inherent biases. Second, it is a single‐center study, which may reflect patterns of referral to our hospital. However, the inclusion of all patients diagnosed with pancreatic cancer may minimize this limitation. Third, the diagnosis of VsT was retrospective, based upon review of radiologic exams with search for associated symptoms on consultation of medical records. Fourth, a quarter (27%) of patients did not have a histologic diagnosis of pancreatic adenocarcinoma. In these patients, all with multiple distant metastases and without cholangitis or cirrhosis, the diagnosis was based on the presence of a pancreatic tumor and serum carbohydrate antigen 19.9 (CA 19.9) >1,000 U/mL, previously shown to have nearly 100% diagnostic specificity for adenocarcinoma of the pancreas 36, 37.
Despite these limitations, our results do suggest that the ONKOTEV score stratifies VTE risk in patients with pancreatic cancer and may identify outpatients eligible for primary thromboprophylaxis, particularly those with ONKOTEV score ≥2. Patients with pancreatic cancer with an ONKOTEV ≥2 (43.6%, 72 of 165) had an incidence of VTE of 58% (42 of 72) and may benefit from primary thromboprophylaxis, with a risk of major bleeding of less than 2% (0.1% in SAVE‐ONCO, 0.7% in PROTECHT, 1% in CASSINI, 1.4% in CONKO‐004, and 1.7% in AVERT trials) 20, 21, 38, 39, 40.
Conclusion
In a retrospective cohort of 165 patients with pancreatic cancer, we documented the value of the ONKOTEV score for stratification of the risk of VTE (50.9% for ONKOTEV score of 2; 82.4% for ONKOTEV score of 3). The risk of VTE can be further increased by radiologic evidence of blood vessel invasion. We suggest that such patients, even if ambulatory, should be considered for primary thromboprophylaxis, particularly if they have a good performance status, no increased hemorrhagic risk and are motivated to adhere to VTE prevention.
Author Contributions
Conception/design: João Godinho, Mafalda Casa‐Nova, João Moreira‐Pinto, Pedro Simões, Francisco Paralta Branco, Luísa Leal‐Costa, Ana Faria, Fábio Lopes, José Alberto Teixeira, José Luís Passos‐Coelho
Provision of study material or patients: João Godinho, Mafalda Casa‐Nova, João Moreira‐Pinto, Pedro Simões, Francisco Paralta Branco, Ana Faria, Fábio Lopes, José Alberto Teixeira, José Luís Passos‐Coelho
Collection and/or assembly of data: João Godinho, Mafalda Casa‐Nova, João Moreira‐Pinto, Pedro Simões, Francisco Paralta Branco, Luísa Leal‐Costa, Ana Faria, Fábio Lopes, José Alberto Teixeira, José Luís Passos‐Coelho
Data analysis and interpretation: João Godinho, Mafalda Casa‐Nova, João Moreira‐Pinto, Pedro Simões, Francisco Paralta Branco, Luísa Leal‐Costa, Ana Faria, Fábio Lopes, José Alberto Teixeira, José Luís Passos‐Coelho
Manuscript writing: João Godinho, Mafalda Casa‐Nova, João Moreira‐Pinto, Pedro Simões, Francisco Paralta Branco, Luísa Leal‐Costa, Ana Faria, Fábio Lopes, José Alberto Teixeira, José Luís Passos‐Coelho
Final approval of manuscript: João Godinho, Mafalda Casa‐Nova, João Moreira‐Pinto, Pedro Simões, Francisco Paralta Branco, Luísa Leal‐Costa, Ana Faria, Fábio Lopes, José Alberto Teixeira, José Luís Passos‐Coelho
Disclosures
João Godinho: Grunenthal (SAB); Mafalda Casa‐Nova: Roche, Pfizer, Merck (SAB), AstraZeneca, Tesaro, Novartis (H). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Acknowledgments
We would like to thank Dr. Miguel Barbosa for challenging us to review and present these data. Funding for this work was provided by Leo Pharma. Leo Pharma had no role in the collection, analysis, and interpretation of data, writing of the manuscript, or in the decision to submit the paper for publication.
Disclosures of potential conflicts of interest may be found at the end of this article.
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