Risk Prediction and Treatment of LE-DVT in Patients with Chronic Radiation Intestinal Injury: A Retrospective Case–Control Study

Introduction

Radiotherapy is among the most effective treatments for pelvic malignancy, with 0.8~2.4 million patients worldwide estimated to require radiotherapy for pelvic cancer in 2020 alone.^1–4 However, radiation-induced intestinal injury (RII) is an unavoidable side effect and the most common complication of pelvic malignancy radiation, damaging the small and/or large intestine.⁵ According to the end time of radiotherapy, RII is divided into acute (less than 3 months after radiotherapy, ARII) and chronic (more than 3 months after radiotherapy, CRII) types. Ninety percent of patients present with ARII, and subsequently, 5% to 55% develop CRII post-pelvic radiotherapy.^6–8 Most of the symptoms of ARII are transient, self-healing, and relieved within 3 months. While CRII often emerges 12~24 months after the end of radiotherapy, it is progressive and difficult to reverse.^9,10 The main clinical presentations of CRII are intestinal obstruction, diarrhea, bleeding, abdominal cramping, anal pain, perforation, necrosis, abscess, fistulas, strictures, severe anemia, chronic malabsorption, and even death, seriously impairing quality of life.^11,12 Chronic radiation proctitis (CRP) is another term used to describe the involvement of the rectum and sigmoid colon, with the most prominent characteristic being bleeding, accounting for > 80% of CRP patients.^13,14

Lower extremity deep venous thrombosis (LE-DVT) is a common condition and major cause of morbidity and mortality worldwide. LE-DVT lesions can detach and embolize into the heart or lung, causing cardiopulmonary embolism or even death. Numerous studies have demonstrated that DVT is a complex multifactorial disease influenced by several risk factors, including surgery and trauma, prolonged immobilization, myeloproliferative disorders, pregnancy and postpartum status, weight, age, smoking status and corticosteroid treatment.^15–17 In addition, radiotherapy and cancer increase the risk of developing DVT,^18–20 and the reported cumulative incidence of venous thrombosis in cancer patients is 1–8%.²¹ Moreover, after radiotherapy, changes in the structure of the pelvic tissue, the blood composition and the vessel wall are more rapid than those of fibrosis,^22,23 and radionecrosis and granulation of the small lymphatic vessels, lymph nodes, and soft tissue around vessels following radiotherapy can lead to the accumulation of protein-rich fluid in soft tissues secondary to inadequate lymphatic drainage.^23–25 Given the serious potential consequences of LE-DVT, knowing more about its prevalence in CRII patients is extraordinarily important. In addition, bleeding is a common symptom of CRII. If LE-DVT and bleeding simultaneously occur in one CRII patient, hemostasis and anticoagulation therapy will be conducted,²⁶ which is a therapeutic contradiction and will greatly increase the difficulty of treatment.

To the best of our knowledge, studies regarding the occurrence of LE-DVT and risk factors for developing LE-DVT in CRII patients are still scarce. Thus, to better prevent and treat CRII complicated with LE-DVT, the incidence of and risk factors for LE-DVT in CRII patients were retrospectively analyzed in this study, and an appropriate treatment strategy was explored.

Materials and Methods

Patients

Hospitalized CRII patients in our hospital from November 2011 to October 2018 were retrospectively included. The diagnostic criteria of CRII were as follows: three months after pelvic malignancy radiation; one or multiple symptoms of intestinal obstruction, diarrhea, bleeding, abdominal cramping, anal pain, perforation, necrosis, abscess, fistulas, strictures, severe anemia, etc.; mucosal fragility, pallor, spontaneous bleeding, telangiectasias, mucosal edema, strictures, fistulas, or ulcerations as observed under endoscopy; and diagnosis by examinations such as magnetic resonance imaging (MRI) and computed tomography (CT). Hospitalized CRII patients needed to satisfy at least one of the following conditions: moderate to severe bleeding evaluated according to the modified Subjective Objective Management Analysis (SOMA, Table 1)^27,28 or severe complications with intestinal obstruction, perforation, necrosis, abscess, fistulas, strictures, severe anemia (hemoglobin (Hb) < 70 g/L), and chronic malabsorption, etc. Anemia was defined as a Hb level <120 g/L for males and <110 g/L for females and categorized into mild anemia (Hb≥90 g/L), moderate anemia (Hb ≥70~<90 g/L), and severe anemia (Hb <70 g/L), as shown in Table 1. In this study, the inclusion criteria were as follows: diagnosis of CRII; hospitalization mainly for the treatment of CRII; and symptoms of DVT in the lower limbs. The exclusion criteria were as follows: acute radiation-induced intestinal injury (less than 3 months after radiotherapy, ARII); previous blood-related diseases or severe coagulation disorders; and incomplete clinical data. From November 2011 to October 2018, 737 hospitalized RII patients were screened, and a total of 608 CRII patients were included in this study (Figure 1). The clinical data of each included patient were carefully collected.

Table 1 Modified Subjective/Objective Management Analysis System to Assess the Severity of Bleeding

Figure 1 Flow chart of patient selection.

Data Collection

CRII patients with suspicious symptoms of LE-DVT such as edema, and pain in the lower extremity etc. were routinely examined by bilateral lower extremity venous Doppler ultrasonography to identify whether there was LE-DVT or not. Clinical data were compared between patients with LE-DVT (observation group) and patients without LE-DVT (control group). The following data were compared: age, sex, body mass index (BMI), cardiovascular and cerebrovascular diseases, diabetes mellitus, blood transfusion history, smoking status, surgical history, recent surgical history, hemostasis drug use, tumor recurrence or metastasis, time to the end of radiotherapy, corticosteroid treatment, radiotherapy dose, Hb level, blood platelet count (BPC), mean platelet volume (MPV), white blood cell (WBC) count, and albumin (ALB) level. The clinical data and laboratory values of the patients were collected initially after admission. Then, the risk factors for developing LE-DVT in CRII patients were retrospectively investigated. In addition, CRII patients with bleeding were graded at three levels according to the modified SOMA to assess the severity of bleeding.

Statistical Analysis

Data analysis in this study was performed using SPSS software, version 19.0 (Chicago, IL, USA). Continuous variables are expressed as the mean ± SD or median (interquartile range, IQR) and were compared using the t-test or Mann–Whitney U-test as appropriate. Categorical variables are expressed as numbers and percentages and were compared using Fisher’s test or the χ² test as appropriate. Variables that were significantly different between groups in the univariate analysis were included in the multivariate logistic regression model in a stepwise manner to assess the associations between potential risk factors and LE-DVT. For the independent risk factors, the best cutoff values for distinguishing between CRII patients with and without LE-DVT were assessed by receiver operating characteristic (ROC) curve analyses. A two-sided p<0.05 was considered statistically significant.

This work is reported in line with the STROCSS criteria.

Results

Demographics and Characteristics

In this study, the primary cancers of the CRII patients included cervical cancer (n=460), endometrial cancer (n=29), ovarian cancer (n=7), vaginal cancer (n=4), prostate cancer (n=24), testicular cancer (n=1), rectal cancer (n=77), anal cancer (n=3), and colon cancer (n=1). Of the 608 included patients, there were 528 (86.8%) CRP patients, including 439 (83.1%) patients with bleeding, and 387 (63.7%) CRII patients who presented with anemia (shown in Table 2); anemia was significantly associated with thrombocytosis (p<0.001).

Table 2 Bleeding-Related Data of the Included CRII Patients

Among the 608 patients eligible for this study, 94 (15.5%) CRII patients had suspicious symptoms of LE-DVT. After confirmation by bilateral lower extremity venous Doppler ultrasonography, 32 patients with LE-DVT were identified. Thus, the prevalence of LE-DVT among all of the CRII patients hospitalized after pelvic malignancy radiation was 5.3% (32/608). Among these CRII patients with LE-DVT, 8 cases affected the left lower limb, 13 affected the right lower limb, and 11 affected both lower limbs. The age of these patients was 57±11 years old, with 3 males and 29 females; the median time to presentation of LE-DVT was 15 months after radiotherapy. The primary cancers of the CRII patients with LE-DVT included cervical cancer (n=27), endometrial cancer (n=1), testicular cancer (n=1), and rectal cancer (n=3). The incidence of LE-DVT among CRII patients who had ever suffered from cervical cancer was 5.9% (27/460). In addition, 65.6% (21/32) of patients had rectal bleeding. After grading the hemorrhagic patients with LE-DVT according to SOMA, we found that 12.5% (4/32) of patients had grade 1 bleeding, 46.9% (15/32) had grade 2 bleeding, and 6.3% (2/32) had grade 3 bleeding. Furthermore, the anemic degree of the patients was also evaluated according to the Hb level (see Table 1). There were 29 (90.6%) anemic patients with LE-DVT, with 53.1% having moderate anemia and 21.9% having severe anemia (listed in Table 2).

Comparisons of CRII Patients with and without LE-DVT

The associations of the clinical data of the patients with and without LE-DVT are listed in Table 3. In the univariate analysis, significantly larger proportions of the patients with a recent surgical history (≤6 months) (31.4% vs 8.7%, p<0.001), a history of hemostatic drug use (53.1% vs 31.3%, p=0.010), tumor recurrence or metastasis (40.6% vs 17.0%, p =0.001), corticosteroid treatment (56.3% vs 26.7%, p<0.001), an ALB level ≤35 g/L (56.3% vs 24.8%, p<0.001), an elevated WBC count [(5.8 (4.8–10.6) vs 5.0 (4.0–6.5), p=0.003)], and a low Hb level [(80.2±16.1 vs 100.4±23.2, p<0.001)] were found in the observation group than in the control group. In contrast, there was no significant difference in age, BMI, cardiovascular and cerebrovascular disease, diabetes mellitus, surgical history, smoking history, time to the end of radiotherapy, BPC, or MPV between the two groups.

Table 3 Characteristics of the CRII Patients with or without LE-DVT

Variables of potential risk factors that were significantly different between the groups were included in the multivariate logistic regression analysis. Table 4 shows that a recent surgical history (≤6 months) (OR=5.761, 95% CI: 2.506~13.246, p<0.001), tumor recurrence or metastasis (OR=3.049, 95% CI: 1.398~6.648, p=0.005) and the Hb level (OR=0.960, 95% CI: 0.942~0.979, p<0.001) were significantly associated with the occurrence of LE-DVT. The results suggest that a recent surgical history, tumor recurrence or metastasis and a low Hb level independently increased the risk of LE-DVT in CRII patients.

Table 4 Multivariate Logistic Regression Analysis for Developing LE-DVT in CRII Patients After Pelvic Malignancy Radiation

ROC Curve of Independent Factors

ROC curve analysis was used to evaluate the potency of the identified independent factors for predicting the occurrence of LE-DVT in CRII patients and compare the potential prognostic variables (Figure 2). The results showed that the area under the ROC curve (AUC) of the merged risk score for predicting the occurrence of LE-DVT in CRII patients was significantly higher [0.822 (95% CI: 0.789~0.852)] than that of the other variables, such as a recent surgical history ≤6 months [0.628 (95% CI: 0.589~0.667), p<0.0001], tumor recurrence or metastasis [0.618 (95% CI: 0.578~0.657), p<0.0001], and the Hb level [0.756 (95% CI: 0.688~0.824), p=0.024]. The cutoff value for the Hb level was 82.5 g/L (sensitivity=71.9%, specificity=75.5%).

Figure 2 ROC curve of independent factors for predicting LE-DVT development in CRII patients after pelvic malignancy radiation and comparison with the potential prognostic variables. Abbreviations: ROC, receiver operating characteristic; AUC, area under the receiver-operating characteristic curve; Hb, hemoglobin.

Treatment

To investigate the treatment strategies adopted for hemorrhagic patients with LE-DVT in this study, hemorrhagic CRII patients with LE-DVT were followed up for at least 1 year. We found that because of uncontrollable bleeding, colostomy was performed in 61.9% (13/21) of hemorrhagic CRII patients with LE-DVT, which was significantly higher than the corresponding proportion of hemorrhagic CRII patients without LE-DVT (17.5%, 73/418). In addition, among the remaining 8 hemorrhagic CRII patients with LE-DVT, 3 patients underwent bowel resection because of unendurable pain or fistula, and the other 5 received no surgery. Moreover, after colostomy, obvious bleeding remission was rapidly observed in 11 (84.6%) hemorrhagic CRII patients with LE-DVT, and LE-DVT disappeared or improved in all these patients following anticoagulation therapy or with vena cava filter or stent placement (LE-DVT obviously improved in 2 patients and disappeared in 1 following anticoagulation therapy and was remarkably relieved in 1 patient and cured in 2 patients following vena cava filter or stent placement with anticoagulation therapy). In contrast, in the 5 hemorrhagic CRII patients with LE-DVT treated without colostomy, bleeding existed for at least one year. Unfortunately, the follow-up LE-DVT treatment data from the remaining hemorrhagic CRII patients with LE-DVT were unavailable because there were no ultrasonic examinations after the patients were treated or we could not contact the patient.

Discussion

In the present study, the prevalence of symptomatic LE-DVT after pelvic malignancy radiation in the CRII patients we evaluated was 5.3%, which is much higher than that in the general population because these patients had a history of pelvic radiation therapy and cancer.²⁹ In this study, only 94 CRII patients with suspicious symptoms of LE-DVT, such as edema and pain in the lower extremities, were tested to verify the presence of LE-DVT, while other patients may have had LE-DVT but showed no symptoms. It has been reported that occult DVT is also more common in patients with cancer.³⁰ Therefore, the occurrence of LE-DVT in CRII patients after pelvic malignancy radiation might be underestimated. More attention should be given to identifying and preventing LE-DVT in CRII patients. Therefore, this study investigated the associated risk factors for the development of LE-DVT in CRII patients. A history of hemostatic drug use, an ALB level less than 35 g/L, an inflammatory cell count (WBC count), and the use of corticosteroids, such as hexadecadrol and budesonide, were obviously associated with the development of LE-DVT in CRII patients. Previously, it has been reported that a history of hemostatic drug use aggravates the hypercoagulable state and hypoalbuminemia and that corticosteroids significantly promote DVT.³¹ Growing evidences have demonstrated that inflammation triggers a variety of responses that lead to increased coagulation and thrombosis.^32,33 Our study is consistent with the previous studies.

Our results showed that a recent surgical history (≤6 months) was independently related to the development of LE-DVT in CRII patients, which may be due to prolonged immobilization. It has been reported that surgery and trauma indeed increase the risk of developing DVT, and surgical operations prolong immobilization.¹⁶ Our results are consistent with those of a previous study. A previous study declared that cancer creates a hypercoagulable state and that the risk of developing DVT is much higher in patients with active cancer.³⁴ The incidence of VTE in patients with cancer is estimated to be 4–7 times higher than that in patients without cancer.^35,36 In this study, we also found that the proportion of tumor recurrence or metastasis in the observation group (40.6%) was much higher than that in the control group (17.0%), and the results showed that tumor recurrence or metastasis was an independent risk factor for LE-DVT in CRII patients.

Moreover, a lower Hb level was another independent risk factor for LE-DVT in CRII patients. Of the included patients in this study, 86.8% were CRP patients, and 83.1% (439/528) and 63.6% (336/528) of the CRP patients were hemorrhagic and anemic, respectively. In addition, 90.6% of the anemic CRP patients had LE-DVT, of whom 75% had moderate to severe anemia (Table 2). Previously, it has been proven that anemia promotes DVT formation because anemia is considered a hyperkinetic state that disturbs the expression of endothelial adhesion molecule genes and can result in endothelial injuries that subsequently result in thrombus formation.³⁷ In this study, the main cause of anemia in patients was hemorrhage, which may give rise to iron deficiency and possibly secondary thrombocytosis and thus lead to an increased thromboembolic risk.^38,39

In the present study, among the 32 CRII patients with LE-DVT, 21 (65.6%) presented with bleeding, and 90.6% presented with anemia. Hemostasis and anticoagulation therapy were needed for the CRII patients suffering from bleeding and LE-DVT simultaneously, which was a paradox and greatly increased the difficulty of treatment. Therefore, detecting LE-DVT in CRII patients earlier and maintaining the treatment balance are extremely important.

It has been reported that if CRII patients suffer from severe intractable bleeding refractory to conservative treatments or require blood transfusions because of bleeding, diverting colostomy is a simple, effective and safe procedure that can lead to a higher rate of bleeding remission (94% vs 12%) and obviously increase the Hb level compared to conservative treatment.²⁸ In this study, among the 21 hemorrhagic CRII patients with LE-DVT, 13 patients had recurrent refractory rectal bleeding or even needed blood transfusion; anticoagulation therapies that can aggravate bleeding were cautiously applied and often withdrawn in these patients. Then, these 13 patients underwent colostomy, and obvious bleeding remission rapidly occurred in 11 patients. Thus, subsequent anticoagulation therapy was much safer than either anticoagulation therapy or hemostasis after bleeding remission, and LE-DVT was indeed alleviated or cured after colostomy and subsequent anticoagulation therapy in some patients according to our follow-up data. However, further studies must be conducted to investigate the effects of colostomy in hemorrhagic CRP patients with LE-DVT because of the small number of these patients until now.

However, our research has some weaknesses. One limitation is that only CRII patients with symptoms of DVT in the lower limbs were examined. Second, only hospitalized CRII patients were included, which inevitably involves patient selection bias. Third, this study is limited by the small number of CRII patients with LE-DVT and hemorrhagic CRII patients with LE-DVT treated by colostomy. Fourth, our study is limited by a lack of access to complete and long-term follow-up data on the treatment of CRII patients with LE-DVT. Further studies will be conducted to confirm our findings and further investigate the effect of colostomy in CRII patients with LE-DVT.

Conclusion

The incidence of LE-DVT was 5.3% in CRII patients after pelvic malignancy radiation, and approximately 15.5% of CRII patients had suspicious symptoms of LE-DVT in the lower limbs. A recent surgical history (≤6 months), tumor recurrence or metastasis and a reduced Hb level were significantly associated with the development of LE-DVT. These characteristics have potential as diagnostic markers to assist doctors in predicting the presence of LE-DVT in CRII patients even if no suspicious symptoms of LE-DVT are observed. In addition, colostomy might be a good choice for treating intractable hemorrhagic CRII in patients with LE-DVT, in whom it was much safer to adopt anticoagulant therapy after colostomy, followed by obvious bleeding remission. This may assist the doctors in making clinical decisions when treating hemorrhagic CRII with LE-DVT.