Prevalence of venous thromboembolism at pretreatment screening and associated risk factors in 2086 patients with gynecological cancer
Abstract
Aim
Postoperative pulmonary embolism can be a fatal surgical complication and is thought to occur secondary to asymptomatic venous thromboembolism (VTE) that exists preoperatively in some patients. The purpose of this study was to clarify the frequency and risk factors of pretreatment VTE in gynecological cancer patients.
Methods
This study investigated 2086 patients with gynecological cancer (cervix, n = 754; endometrium, n = 862; ovary, n = 470) who underwent initial treatment between 2004 and 2017. Pretreatment VTE screening was performed with D‐dimer (DD) levels in these patients. Based on this, the associated risk factors were retrospectively analyzed.
Results
Pretreatment VTE was discovered in 7.3% of patients with cervical cancer, 11.5% of those with endometrial cancer and 27.0% of those with ovarian cancer. Significant independent risk factors were: age greater than or equal to 60 years and tumor long diameter greater than or equal to 40 mm for cervical cancer; age greater than or equal to 60 years, stage III/IV advanced disease, clear cell carcinoma and tumor long diameter greater than or equal to 60 mm for endometrial cancer; and age greater than or equal to 60 years, clear cell carcinoma and massive ascites for ovarian cancer.
Conclusion
Pretreatment asymptomatic VTE is very frequent in gynecological cancer patients. It may be beneficial to consider measuring DD or performing venous ultrasonography in patients with the above risk factors.
Introduction
Postoperative symptomatic venous thromboembolism (VTE), especially pulmonary embolism (PE), is a potentially fatal surgical complication. The mortality of patients who develop PE is about 15%,1, 2 and these PE deaths occur within 1 h of onset in approximately 75% of cases and within 48 h in the remaining 25%.3 For PE, the prevention of its onset is crucial.
One of the causes of postoperative symptomatic PE is the exacerbation of pre‐existing asymptomatic VTE. In patients who have developed asymptomatic VTE prior to treatment, iatrogenic symptomatic PE may be induced intraoperatively or postoperatively when prolonged or highly invasive surgery is performed, or when intermittent pneumatic compression is applied to patients without being aware of the presence of VTE. Factors involved in the occurrence of VTE in cancer patients before treatment include: congenital predisposition to thrombophilia, vein displacement caused by the tumor and hemoconcentration due to ascites production, as well as the potential activation of the extrinsic coagulation pathway by tumor‐produced tissue factor (TF) in ovarian cancer, as shown previously by our group.4 It has been reported that the pre‐treatment prevalence of VTE in patients with gynecological malignant tumors is 2.8–4.8% in cervical cancer,5, 6 5.1–9.9% in endometrial cancer5, 7, 8 and 7.1–26.7% in ovarian cancer,5, 9-11 indicating that asymptomatic cases are common. However, none of the reports, including our previous report, that investigated the pretreatment prevalence of VTE through screening included a large enough sample size of patients with gynecological malignant tumors. Since 2004 at our institution, we have been conducting VTE screening using D‐dimer (DD) prior to treatment in patients with gynecological malignant tumors. One of the objectives of this study was to verify whether the prevalence of VTE before treatment is indeed high by analyzing 2086 patients, including those who have already been reported. The DD used in the screening is a degradation product of fibrin and reflects the concentration of fibrin. Elevation of the plasma DD level is thought to be generally associated with the presence of DVT with a positive predictive value of 36–44% and a negative predictive value of 89–100%.12-14 Therefore, while VTE is not necessarily present even when the DD level exceeds the normal upper limit, it can be assumed that the chances of VTE being present are extremely low when the DD level is lower than the normal upper limit.
We previously reported that most cases of VTE prior to treatment in patients with gynecological cancer are asymptomatic.6, 8, 11 Another objective of this study was to verify whether this still holds true with a larger sample size. For many institutions, it may be difficult to perform pretreatment VTE screening in all patients with gynecological cancer. In this situation, there is a method to efficiently screen patients by identifying the risk factors for developing VTE prior to treatment and narrowing down the patients to those with risk factors. Thus, the other objective of this study was to identify such risk factors.
Methods
Patients
This study investigated 2086 consecutive patients with gynecological cancer who underwent initial treatment at the University of Tsukuba Hospital between November 2004 and December 2017, including patients we previously reported (cervical cancer, n = 2726; endometrial cancer, n = 1718; ovarian cancer, n = 6011). There were 754 patients who were pathologically confirmed to have cervical cancer, 862 patients who were pathologically confirmed to have endometrial cancer, and 470 patients who were presumed before treatment to have ovarian cancer, fallopian tube cancer or peritoneal cancer (hereinafter, collectively referred to as “ovarian cancer”) and ultimately diagnosed pathologically with invasive cancer (excluding borderline malignant tumors). Adenocarcinoma of cervical cancer included 18 patients with adenosquamous carcinoma. The 179 patients with serous ovarian cancer included high‐grade serous carcinoma (n = 156) and low‐grade serous carcinoma (n = 23). Six patients with ovarian cancer of unknown histological type responded well to neoadjuvant chemotherapy, though the histological type could not be determined. Table 1 shows a summary of the patients' characteristics. In nearly all patients, factors such as tumor size, tumor extension, lymph node (LN) enlargement and presence of massive ascites were evaluated with imaging examinations, such as magnetic resonance imaging (MRI) and computed tomography (CT). However, CT records in two patients with cervical cancer and MRI and CT records in one patient with ovarian cancer were lost.
| Characteristic | Cervix n = 754 | Endometrium n = 862 | Ovary n = 470 | Total n = 2086 |
|---|---|---|---|---|
| Median (range) | ||||
| Age, years | 50 (24–96) | 59 (19–93) | 57 (16–91) | 56 (16–96) |
| Body mass index, kg/m2 | 22.1 (12.6–40.0) | 23.8 (11.7–78.1) | 21.6 (13.3–50.5) | 22.5 (11.7–78.1) |
| Tumor diameter, mm | 41 (0–165) | 33 (0–300) | 105.5 (0–360) | |
| n of patients (%) | ||||
| FIGO stage | ||||
| I | 302 (40.1) | 523 (60.7) | 154 (32.8) | 979 (46.9) |
| II | 148 (19.6) | 90 (10.4) | 52 (11.1) | 290 (13.9) |
| III | 239 (31.7) | 140 (16.2) | 175 (37.2) | 554 (26.7) |
| IV | 65 (8.6) | 108 (8.6) | 89 (18.9) | 262 (12.6) |
| Unknown | 1 (0.1) | 1 (0.1) | ||
| Histology | ||||
| Squamous | 585 (77.6) | 2 (0.2) | 1 (0.2) | 588 (29.1) |
| Adeno | 128 (17.0) | 786 (91.2) | 400 (85.1) | 1314 (62.9) |
| Serous | 4 (3.1) | 38 (4.4) | 179 (38.1) | 221 (17.0) |
| Clear cell | 2 (1.6) | 32 (3.7) | 139 (29.6) | 173 (13.3) |
| Mucinous | 45 (35.2) | 5 (0.6) | 39 (8.3) | 89 (6.8) |
| Endometrioid | — | 690 (80.0) | 39 (8.3) | 729 (55.9) |
| Endocervical, usual type | 77 (60.2) | — | — | 7 (5.9) |
| Mixed | 0 (0.0) | 21 (2.4) | 4 (0.9) | 25 (1.9) |
| Carcinosarcoma | 0 (0.0) | 24 (2.8) | 7 (1.5) | 31 (1.5) |
| Sarcoma | 0 (0.0) | 15 (1.7) | 1 (0.2) | 16 (0.8) |
| Other | 41 (5.4) | 35 (4.1) | 55 (11.7) | 131 (6.3) |
| Unknown | 0 (0.0) | 0 (0.0) | 6 (1.3) | 6 (0.3) |
- FIGO, International Federation of Gynecology and Obstetrics.
Detection of DVT and PE before treatment
Although the method of measuring DD differed depending on the time period of the study, venous ultrasound imaging (VUI) to identify deep vein thrombosis (DVT) was consistently performed in all patients with ovarian cancer and in patients with cervical cancer or endometrial cancer if their DD level exceeded the upper limit of the institution's standard, the presence of DVT was suspected due to lower limb pain or poor performance status or there was a history of VTE. Although symptomatic VTE had not occurred throughout all treatment courses, there was only one patient with cervical cancer whose DD had not been measured prior to starting the treatment.
Ultrasonography was performed using an ATL HDI5000 system (Philips Medical Systems, Bothell, WA, USA) equipped with a 3‐ to 7.5‐MHz transducer. Power, pulse repetition frequency and wall thump filter settings were adjusted for venous vascular studies. The iliac, femoral, great saphenous, popliteal, peroneal, posterior tibial and soleal veins were evaluated bilaterally. The iliac and femoral veins were assessed in a supine position, while all other veins were assessed in an upright position. All veins were imaged on both transverse and long‐axis views. Venous lumina were observed while searching for thrombus by manual compression with the transducer and color Doppler imaging. For evaluation of intrapelvic veins, reactions during the Valsalva maneuver were also observed. A lack of reaction during the Valsalva maneuver was suspected to represent proximal venous flow disturbance. All patients with gynecological cancer underwent comprehensive imaging studies using enhanced abdominal and pelvic CT to detect metastatic tumor and thrombus in iliac veins and the inferior vena cava. These methods were almost identical to methods in our previous reports.6, 8, 11
When DVT was discovered through VUI or contrast‐enhanced CT, the patient was further investigated for the presence of PE. From 2004 to 2007, this examination was conducted using pulmonary perfusion scintigraphy using m99Tc, but not in four ovarian cancer patients who were unlikely to have PE due to the discovery of only an old organized thrombus limited to the soleal veins. During the transitional period from 2008 to 2009, either scintigraphy or contrast‐enhanced CT was performed. Since 2010, contrast‐enhanced CT has been used to examine for PE. Management of pre‐treatment VTE was based on our previous report.15
Extraction of risk factors
Data on the following factors were collected from patient records and used in univariate and multivariate analyses: age; body mass index; FIGO stage; histology; pelvic and/or paraaortic LN swelling (short diameter) on CT; size of tumor (long diameter) on MRI; tumor extension on CT and/or MRI and massive ascites (massive ascites was defined as centralization detected by CT in this study) on CT. In addition to these factors, for endometrial cancer, data on ovarian metastasis and direct myometrial invasion on MRI were used. Only three patients with cervical cancer had massive ascites, and analyses were not conducted in these patients, since VTE was not present. Using a logistic model for each type of primary tumor, significance tests were conducted. Factors with P < 0.05 on univariate analysis were identified, and these factors were investigated by multivariate analysis. Differences in proportions were evaluated by the Fisher's exact test. All significance tests were conducted using the SAS version 9.4 software (SAS Institute, Cary, NC, USA).
Results
Plasma level of DD and prevalence of VTE before treatment
The median (range) plasma DD level was 0.7 (0.1–103.5) μg/mL in all patients, 0.6 (0.1–20.0) μg/mL in cervical cancer patients, 0.7 (0.1–90.2) μg/mL in endometrial cancer patients and 2.4 (0.1–103.5) μg/mL in ovarian cancer patients. DD exceeded the upper limit of normal (ULN) in 772 of all 2085 patients whose DD was measured (37.0%), 178 of 754 cervical cancer patients (23.6%), 241 of 862 endometrial cancer patients (32.4%) and 353 of 470 ovarian cancer patients (75.1%). With comprehensive diagnostic imaging and VUI, VTE existing prior to treatment was discovered in 281 gynecological cancer patients (13.5%), 55 cervical cancer patients (7.3%), 99 endometrial cancer patients (11.5%) and 127 ovarian cancer patients (27.0%), and these frequencies were statistically different among cancer types (Table 2). Of the patients with DD values less than or equal to ULN, VTE was discovered in 3 patients (0.4%), 10 patients (1.2%), and 6 patients (1.3%) with cervical cancer, endometrial cancer and ovarian cancer, respectively. Of the 281 patients with pretreatment VTE, 276 (98.2%) were asymptomatic, and only 5 had developed symptomatic thrombosis (lower limb pain, n = 1; lower limb pain + oedema, n = 1; respiratory discomfort, n = 1; cerebral infarction, n = 2). Of the two patients who had developed cerebral infarction, one patient had PE and the other patient had both DVT and PE, but VTE symptoms were not observed. The locations of DVT in 276 patients with asymptomatic VTE are summarized in Table 3, and the distribution was similar among cancer types. Among the five symptomatic patients, four patients had proximal DVT (femoral vein) and four patients had tumor of clear cell histology (three with ovarian cancer and one with endometrial cancer). Presence of femoral DVT and clear cell histology of tumor were both significantly associated with symptomatic pretreatment VTE (P = 0.0004 and 0.008, respectively; data not shown). Of the 64 patients with pretreatment PE, 3 patients (5%) were asymptomatic (2 with endometrial cancer and 1 with ovarian cancer).
| Cervix n = 754 n (%) | Endometrium n = 862 n (%) | Ovary n = 470 n (%) | P‐value | Total n = 2086 n (%) | |
|---|---|---|---|---|---|
| Deep vein thrombosis (DVT) | 54 (7.2) | 96 (11.1) | 124 (26.4) | 2.2E−16 | 274 (13.1) |
| DVT alone | 47 (6.2) | 80 (9.3) | 89 (18.9) | 3.9E−11 | 216 (10.4) |
| Pulmonary embolism (PE) | 8 (1.1) | 18 (2.1) | 38 (8.1) | 1.7E−10 | 64 (3.1) |
| PE alone | 1(0.1) | 2 (0.2) | 3 (0.6) | 0.24 | 6 (0.3) |
| DVT + PE | 7 (0.9) | 17 (2.0) | 35 (7.4) | 8.5E−10 | 59 (2.8) |
| Any venous thromboembolism | 55 (7.3) | 99 (11.5) | 127 (27.0) | 2.2E−16 | 281 (13.5) |
| Location | Cervix n = 55 | Endometrium n = 97 | Ovary n = 124 | Total n = 276 |
|---|---|---|---|---|
| n (%) | ||||
| IVC | 0 (0) | 2 (2) | 0 (0) | 2 (1) |
| Great saphenous vein | 0 (0) | 0 (0) | 4 (3) | 4 (1) |
| Small saphenous vein | 0 (0) | 1 (1) | 3 (2) | 4 (1) |
| Lower leg††
Details unkown. |
1 (2) | 3 (3) | 2 (2) | 6 (2) |
| Iliac vein | 5 (9) | 2 (2) | 5 (4) | 12 (4) |
| Popliteal vein | 6 (11) | 9 (9) | 8 (6) | 23 (8) |
| Femoral vein | 7 (13) | 6 (6) | 12 (10) | 25 (9) |
| Tibial vein | 10 (18) | 10 (10) | 18 (15) | 38 (14) |
| Peroneal vein | 13 (24) | 28 (29) | 33 (27) | 74 (27) |
| Soleal vein | 39 (71) | 71 (73) | 97 (78) | 207 (75) |
- † Details unkown.
- DVT, deep vein thrombosis; VTE, venous thromboembolism; IVC, inferior vena cava.
Risk factors for VTE before treatment
In cervical cancer patients, univariate analysis identified age greater than or equal to 60 years, FIGO stage III/IV, presence of swollen LN with short diameter greater than 10 mm, tumor diameter greater than 40 mm, and presence of extrauterine extension of tumor as significant risk factors, and multivariate analysis confirmed that age and tumor diameter were independent and significant risk factors for VTE before treatment (Table 4). In endometrial cancer patients, univariate analysis identified age greater than or equal to 60 years, FIGO stage III/IV, clear cell carcinoma, presence of swollen LN with short diameter greater than 10 mm, tumor diameter greater than 60 mm, presence of extrauterine extension of tumor, massive ascites, ovarian metastasis and muscle invasion of greater than or equal to 1/2 as significant risk factors, and multivariate analysis confirmed that age, disease stage, clear cell carcinoma and tumor diameter were independent and significant risk factors for VTE before treatment (Table 4). In ovarian cancer patients, univariate analysis identified age greater than or equal to 60 years, presence of massive ascites and histological type of clear cell carcinoma as significant risk factors, and multivariate analysis confirmed that these three factors were independent and significant risk factors for VTE before treatment (Table 4).
| Variable | Incidence | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|
| ORs (95% CI) | P‐value | RR (95% CI) | P‐value | ||
| Cervical cancer | |||||
| Age (years) | |||||
| <60 | 14/511 (2.7%) | Reference | Reference | ||
| ≥60 | 41/243 (16.9%) | 7.21 (3.84–13.51) | <0.0001 | 6.68 (3.48–13.54) | <0.0001 |
| Body mass index (kg/m2) | |||||
| <25 | 43/573 (7.5%) | Reference | |||
| ≥25 | 12/179 (6.7%) | 0.89 (0.46–1.72) | 0.72 | ||
| FIGO stage | |||||
| I | 9/302 (3.0%) | Reference | |||
| II | 9/148 (6.1%) | 2.04 (0.83–5.03) | 0.13 | ||
| III | 21/239 (8.8%) | 2.95 (1.38–6.32) | 0.003 | ||
| IV | 16/65 (24.6%) | 8.26 (3.82–17.87) | <0.0001 | ||
| I/II | 18/450 (4.0%) | Reference | Reference | ||
| III/IV | 37/304 (12.2%) | 3.04 (1.77–5.24) | <0.0001 | 1.02(0.46–2.18) | 0.96 |
| Histology | |||||
| Squamous cell carcinoma | 42/585 (7.2%) | Reference | |||
| Adenocarcinoma | 11/128 (8.6%) | 1.19 (0.63–2.26) | 0.59 | ||
| Pelvic and/or paraaortic LN swelling on CT | |||||
| <10 mm | 20/385 (5.2%) | Reference | Reference | ||
| ≥10 mm | 35/367 (9.5%) | 1.84 (1.08–3.12) | 0.02 | 1.05(0.53–2.11) | 0.89 |
| Size of cervival tumor on MRI | |||||
| <40 mm | 8/360 (2.2%) | Reference | Reference | ||
| ≥40 mm | 47/394 (11.9%) | 5.34 (2.57–11.20) | <0.0001 | 5.41 (2.31–14.01) | <0.0001 |
| Tumor extension on CT and/or MRI | |||||
| Localized to the uterus | 13/337 (3.9%) | Reference | Reference | ||
| Extrauterine spread | 42/417 (10.1%) | 2.61 (1.43–4.78) | 0.0008 | 1.19 (0.53–2.59) | 0.67 |
| Endometrial cancer | |||||
| Age (years) | |||||
| <60 | 35/453 (7.7%) | Reference | Reference | ||
| ≥60 | 64/409 (15.7%) | 2.22 (1.43–3.43) | 0.0003 | 2.06 (1.27–3.37) | 0.003 |
| Body mass index (kg/m2) | |||||
| <25 | 64/503 (12.7%) | Reference | |||
| ≥25 | 35/359 (9.8%) | 0.74 (0.48–1.15) | 0.17 | ||
| FIGO stage | |||||
| I | 27/523 (5.2%) | Reference | |||
| II | 7/90 (7.8%) | 1.51 (0.68–3.36) | 0.34 | ||
| III | 25/140 (17.9%) | 3.46 (2.01–5.77) | <0.0001 | ||
| IV | 40/108 (37.0%) | 7.17 (4.61–11.16) | <0.0001 | ||
| I/II | 34/613 (5.6%) | Reference | Reference | ||
| III/IV | 65/248 (26.2%) | 4.73 (3.21–6.96) | <0.0001 | 0.51 (0.26–1.00) | 0.05 |
| Histology | |||||
| Endometrioid | 59/690 (8.6%) | Reference | |||
| Serous | 11/38 (29.0%) | 3.39 (1.94–5.90) | 0.0005 | ||
| Mucinous | 2/5 (40.0%) | 4.68 (1.56–14.07) | 0.06 | ||
| Clear | 12/32 (37.5%) | 4.39 (2.63–7.30) | <0.0001 | ||
| Non‐clear | 87/830 (10.5%) | Reference | Reference | ||
| Clear | 12/32 (37.5%) | 3.58 (2.19–5.84) | <0.0001 | 3.70 (1.51–8.70) | 0.004 |
| Pelvic and/or paraaortic LN swelling on CT | |||||
| <10 mm | 55/714 (7.7%) | Reference | Reference | ||
| ≥10 mm | 44/148 (29.7%) | 3.86 (2.71–5.50) | <0.0001 | 0.78 (0.41–1.47) | 0.44 |
| Size of endometrial tumor on MRI | |||||
| <60 mm | 52/688 (7.6%) | Reference | Reference | ||
| ≥60 mm | 47/174 (27.0%) | 3.57 (2.50–5.11) | <0.0001 | 1.77 (1.02–3.04) | 0.04 |
| Tumor extension on CT and/or MRI | |||||
| Localized to the uterus | 34/628 (5.4%) | Reference | Reference | ||
| Extrauterine spread | 65/234 (27.8%) | 5.13 (3.49–7.55) | <0.0001 | 0.49 (0.22–1.09) | 0.08 |
| Massive ascites on CT | |||||
| Absent | 87/829 (10.5%) | Reference | Reference | ||
| Present | 12/33 (36.4%) | 3.46 (2.12–5.67) | 0.0001 | 0.67 (0.29–1.61) | 0.36 |
| Ovarian metastasis on MRI | |||||
| Absent | 25/93 (26.9%) | Reference | Reference | ||
| Present | 74/769 (9.6%) | 2.79 (1.87–4.16) | <0.0001 | 0.78 (0.40–1.49) | 0.45 |
| Direct myometrial invasion on MRI | |||||
| <1/2 | 45/612 (7.4%) | Reference | Reference | ||
| ≥1/2 | 54/250 (21.6%) | 2.94 (2.03–4.24) | <0.0001 | 0.75 (0.44–1.29) | 0.3 |
| Ovarian cancer | |||||
| Age (years) | |||||
| <60 | 48/258 (18.6%) | Reference | Reference | ||
| ≥60 | 79/212 (37.3%) | 2.60 (1.71–3.95) | <0.0001 | 2.88 (1.84–4.56) | <0.0001 |
| Body mass index (kg/m2) | |||||
| <25 | 99/371 (26.7%) | Reference | |||
| ≥25 | 28/99 (28.3%) | 1.08 (0.66–1.78) | 0.75 | ||
| FIGO stage | |||||
| I | 41/154 (26.6%) | Reference | |||
| II | 10/52 (19.2%) | 0.72 (0.39–1.34) | 0.28 | ||
| III | 45/175 (25.7%) | 0.97 (0.67–1.39) | 0.85 | ||
| IV | 31/89 (34.8%) | 1.31 (0.89–1.93) | 0.18 | ||
| I/II | 51/206 (24.8%) | Reference | |||
| III/IV | 76/264 (28.8%) | 1.16 (0.86–1.58) | 0.33 | ||
| Histology | |||||
| Serous | 43/179 (24.0%) | Reference | |||
| Mucinous | 11/39 (28.2%) | 1.17 (0.67–2.06) | 0.59 | ||
| Clear | 46/139 (33.1%) | 1.38 (0.97–1.96) | 0.07 | ||
| Endometrioid | 6/39 (15.4%) | 0.64 (0.29–1.40) | 0.23 | ||
| Non‐clear | 75/321 (23.4%) | Reference | Reference | ||
| Clear | 46/139 (33.1%) | 1.41 (1.04–1.93) | 0.03 | 2.41 (1.49–3.93) | 0.0003 |
| Pelvic and/or paraaortic LN swelling on CT | |||||
| <10 mm | 84/299 (28.1%) | Reference | |||
| ≥10 mm | 43/170 (25.3%) | 0.90 (0.66–1.23) | 0.51 | ||
| Size of ovarian tumor on MRI | |||||
| <100 mm | 53/214 (24.8%) | Reference | |||
| ≥100 mm | 74/255 (29.0%) | 1.17 (0.87–1.59) | 0.3 | ||
| Tumor extension on CT and/or MRI | |||||
| Localized to the uterus | 33/142 (23.2%) | Reference | |||
| Extraovarian spread | 94/327 (28.8%) | 1.24 (0.88–1.75) | 0.21 | ||
| Massive ascites on CT | |||||
| Absent | 71/321 (22.1%) | Reference | Reference | ||
| Present | 56/148 (37.8%) | 1.71 (1.28–2.29) | 0.0005 | 2.27 (1.43–3.61) | 0.0005 |
- Massive ascites was defined as centralization detected by CT in this study. FIGO, International Federation of Gynecology and Obstetrics; N, number.
Examining the risks of developing VTE in all patients, using cervical cancer patients as a reference, the odds ratios in endometrial cancer and ovarian cancer were 1.65 (95% confidence interval [CI]: 1.17–2.33) and 4.71 (95% CI: 3.34–6.62), respectively.
Discussion
We previously reported that the frequency of VTE before starting treatment was 4.8% (n = 272) in cervical cancer,6 9.9% (n = 171) in endometrial cancer8 and 26.7% (n = 60) in ovarian cancer.11 In the present study, we reinvestigated this with a larger sample size and reconfirmed that VTE occurs at a high frequency before treatment in gynecological cancer patients: 7.3% (n = 753) in cervical cancer, 11.5% (n = 862) in endometrial cancer and 27.0% (n = 470) in ovarian cancer (Table 2). The rate of discovering VTE was slightly higher than in the previous report, perhaps because the technology to find DVT using lower limb ultrasound has become more advanced since the time we initially started the screening. According to retrospective chart reviews, the frequency of VTE before starting treatment in gynecological cancer patients was reported to be 43/7562 patients (0.6%)16 and 15/2316 patients (0.6%).17 The percentage is about a twentieth of the present results; however, these retrospective chart reviews are thought to select symptomatic VTE patients and, therefore, cannot be compared to the results from a screening test. Recently, there have been reports of the frequency of VTE before treatment through screening in patients with cancer other than gynecological cancer, and these reports stated that 4.4% (7/160) of gastric cancer patients had VTE, with all 7 being asymptomatic,18 and 16.5% (17/103) of advanced pancreatic cancer patients had VTE, with 14/17 (82.4%) being asymptomatic.19 These frequencies of pre‐treatment VTE are comparable to our results in cervical and endometrial cancers (Table 2), suggesting that patients with non‐gynecological cancer may also have considerable frequencies of asymptomatic VTE before treatment. In a study of bladder cancer patients who underwent radical cystectomy, the screened group (n = 65) and the historical comparison group that did not undergo screening (n = 78) were compared.20 In the screened group, asymptomatic DVT was discovered preoperatively in nine patients (13.9%), only three developed DVT, and none progressed to PE postoperatively as a result of preventive treatments such as placement of an inferior vena cava filter. In contrast, in the historical comparison group, VTE was not discovered in any patients preoperatively, but it developed in 11 patients postoperatively. Six of these patients developed DVT early in the postoperative period; progression to PE was evident in four of these patients, two of whom eventually died.20 This article suggests that the preoperative discovery of asymptomatic VTE and appropriate management may prevent the postoperative onset of fatal PE.
Our results confirmed that there was a significant difference in frequencies of pre‐treatment VTE among gynecological cancer types, being highest in ovarian cancer (Table 2). However, the distribution of the locations of DVT in patients with asymptomatic VTE was similar among cancer types (Table 3), suggesting that the different frequencies among cancer types may be due to not the different anatomical locations of primary organs or the different progression pathways, but possibly rather the different extent of accelerated blood coagulation.
In the present study, being 60 years old or older was identified as an independent and significant risk factor for pre‐treatment VTE development in all three types of primary tumor. Risk evaluation scores for VTE onset such as the Caprini score21 and the Padua score22 also incorporate age as a factor. A potential underlying mechanism for age being an important VTE risk factor may be that hemoconcentration is more likely to occur with increasing age. Massive ascites was also likely identified due to hemoconcentration caused by intravascular dehydration, in addition to the direct compression applied to veins by the ascites. Clear cell carcinoma was identified as an independent and significant risk factor, possibly because clear cell carcinoma has significantly higher TF expression compared to other histological types,4, 23-25 indicating that the extrinsic coagulation pathway may be accelerated. Additionally, stage III/IV advanced cancer, LN enlargement that suggests metastasis and tumor extension beyond the primary organ were identified as independent and significant risk factors for pretreatment VTE, and this may be a consequence of augmentation in blood coagulation through basement membrane destruction and interstitial infiltration caused by tumor extension/metastasis and stimulation from and the immune response to intravascular/intraductal entry.26 It may be beneficial to consider measuring DD or performing VUI in patients with risk factors even at institutions that may have difficulties screening all patients with gynecological malignancies.
This study retrospectively summarized the results from our screening test. The large sample size is an advantage of this study. However, the disadvantages are that, due to the long study period, the measurement method of DD differed depending on the time period. Furthermore, the findings are based on a single‐center, retrospective study. This study demonstrated the high frequency of asymptomatic VTE in gynecological cancer patients before treatment and also clarified the associated risk factors. In the future, it will be necessary to validate these findings in a multicenter, prospective study. We further plan to retrospectively compare the same study population and the historical control group to determine whether the search for VTE before treatment through this screening and management after its discovery contributed to the lowering of the postoperative incidence of potentially fatal PE.
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number JP18K09218 (Grant‐in‐Aid for Scientific Research (C)).
Disclosure
The authors have no conflicts of interest to disclose.
