CRII is a commonly observed side effect of pelvic radiation therapy, with the characteristic pathologic changes are inflammatory disease, endarteritis of arterioles, epithelial atrophy, vascular thrombi, capillary compensatory hyperplasia, ischemia, necrosis, and excessive fibrosis[4]. Because of pelvic radiation therapy and cancer history, the incidence of LE-DVT in CRII patients may increase. Therefore, in the present study, prevalence of LE-DVT in CRII patients after pelvic malignancy radiation we evaluated was 5.3%, which was much higher than that in general population [14].Although the prevalence of LE-DVT was not very high, the issue of CRII patients with LE-DVT and bleeding at the same time was extremely intractable and serious. The result showed (460/608, 75.7%) most of the included patients had cervical cancer, it may be because the treatment strategy of high dose radiation for cervical cancer, correspondingly, the small and large intestines in the pelvic cavity also received relatively high radiation doses and thus damaged [29]. In further, incidence of LE-DVT in CRII patients with cervical cancer we then evaluated was 5.7%, which was in accordance with papers that documented 5.5%–16.7% of LE-DVT in patients with cervical cancer [30-32]. However, in this study, only 94 CRII patients with suspicious symptoms of LE-DVT like edema, pain in the lower extremity etc. were tested to verify the presence of LE-DVT, while other patients may do have LE-DVT but showed no symptom. Therefore, the occurrence of LE-DVT in CRII patients after pelvic malignancy radiation might be underestimated.
As for CRII patients, thromboembolic complications may develop but were overlooked. In order to diagnose possible LE-DVT existing in CRII patients, the associated risk factors of LE-DVT in CRII patients were then investigated. A previous study declared that cancer is a hypercoagulable state, and the risk of developing DVT is much higher in patients with active cancer[33]. Further, hemostasis drug use history willaggravate the hypercoagulable state and hypoalbuminemia significantly increases DVT formation[34]. In this study, significant differences were also observed between the observation and control groups in the proportion of patients who had hemostasis drug use histories, tumor recurrence or metastasis and whose ALB levels were less than 35 g/L. And growing evidence demonstrated that inflammatory triggers a variety of responses that lead to increased coagulation and thrombosis[35, 36]. Our result also showed that the inflammatory cells (WBC) were obviously associated with the development of LE-DVT in CRII patients. In addition, surgery and trauma increased the risk of developing DVT, and surgery operation will prolong immobilized time[17]. And recent surgical history (≤6 months) in our result is indeed independently related to developing LE-DVT in CRII patients. Additionally, this study showed hormone like hexadecadrol or budesonide treatment significantly increase the risk of developing LE-DVT, which was in accordance with the research of Lieber et al[37].
Strikingly, it was very gratifying to find that lower Hb was another independent risk factor for LE-DVT in CRII patients, and ROC curve analysis showed that the AUC of Hb was 0.756, and the cut-off of Hb was 82.5 g/L (sensitivity=71.9%, specificity =75.5%), indicating that Hb was an useful diagnostic indicator forpredicting the presence of LE-DVT.
In this study, of all the included patients, 86.8% were CRP patients. Among these CRP patients, 83.1% (439/528) were hemorrhagic CRP patients, and 63.6% (336/528) were anemic patients. As a previous study reported, bleeding is the most frequently occurring symptom of CRP patients, which account for more than 80% and will probably give rise to anemia[12]. As we all know, Hb is a key maker reflecting whether there exist anemia or not. A level of Hb lower than 82.5 g/mL indicates moderate to severeanemia according to the diagnostic criteria for anemia. Moreover, this study demonstrated that there were 90.6% anemic patients with LE-DVT, of whom 75% patients had moderate to severe anemia. Previously, it was proved that anemia increased DVT forming, because anemia is considered a hyperkinetic state which disturbs endothelial adhesion molecule genes that can lead to thrombus formation, and blood flow augmentation and turbulence can result in the migration of this thrombus, producing artery-to-artery embolism, which can have more severe consequences[38].
The present study showed that among the 32 CRII patients with LE-DVT, 21 (65.6%) were presenting with bleeding and 90.6% with anemia. Hemostasis and anticoagulation therapy were needed for CRII patients suffered from bleeding and LE-DVT simultaneously, which was a paradox and largely increased the difficulty of treatment. Moreover, CRII patients receiving anticoagulation therapy were observed to have a significantly increased incidence of severe anemia compared to that with non-anticoagulation therapy (13.5% vs. 3.7%, p=0.016 <0.05) in this study. In further, according to the experience of our research team, theduration of bleeding was at least more than one or two years once the patients developed the symptom of bleeding. Therefore, how to detect LE-DVT in CRII patients earlier and to maintain the treatment balance is extremely important. Additionally, monitoring Hb also played a key role in the course of treatment of hemorrhagic CRII with LE-DVT.
However, until now nostandard treatment strategies or procedures are established for treating hemorrhagic CRP. According to the experience of our research team, an ascending ladder therapy was adopted as follows. For mild to moderate hemorrhagic CRP, a novel mixture enema (almagate combined with thrombin, epidermal growth factor,metronidazole and hexadecadrol or budesonide) was an effective strategy, with 90% and 69% short-term and long-term effective rates, respectively[39]. For moderate hemorrhagic CRP, argon plasma coagulation is a well-tolerated and effective treatment option[40, 41]. For moderate to severe hemorrhagic CRP without massive ulcers which is refractory to medical management, modified formalin irrigation is an effective and safe method, with an effectiveness rate of 79.1%[42]. Further, if CRP patients suffer from severe intractable bleeding refractory to the above conservative treatments or require blood transfusions because of bleeding, diverting colostomy is a simple, effective and safe procedure, which obtained a higher rate of bleeding remission (94% vs. 12%) and obviously elevated hemoglobin levels, compared to conservative treatment[28]. Moreover, if hemorrhagic CRP patients couldn’t manage after undergoing colostomy and conservative treatment or have fistula or necrosis that with unbearable anal pain, resection of the severe damaged intestine and then colostomy could be a good choice. In addition, these hemorrhagic CRP patients without colostomy were suggested to adopt a low residue and high protein diet.
In this research, among the 21 hemorrhagic CRII patients with LE-DVT, 13 patients had recurrent refractory rectal bleeding or even need blood transfusion, and anticoagulation therapies which will aggravate bleeding were cautious and often withdrawn for these patients. Then, these 13 patients underwent colostomy treatment, and obvious bleeding remission was rapidly found in 11 patients. Thus, subsequent anticoagulation therapy was much safer than either anticoagulation or hemostasis therapy after bleeding remission, and LE-DVTs in some patients were indeed alleviated or cured after colostomy and subsequently anticoagulation therapy, according to our follow-up data. However, further studies must be conducted to investigate effects of colostomy in hemorrhagic CRP patients with LE-DVT because of the small number of these patients until now.
However, our research had some weaknesses. A first limitation was that only CRII patients with symptoms of DVT in the lower limbs were examined. Secondly, the fact that only the hospitalized CRII patients were included which involved an inevitable patient selection bias. Thirdly, this study was limited by the small numbers of CRII patients with LE-DVT and hemorrhagic CRII patients with LE-DVT treated by colostomy. Fourthly, our study was also limited by a lack of access to complete and long-term follow-up data on treatment of the CRII patients with LE-DVT. Further studies will be conducted to confirm our findings and further investigate the effect of colostomy for CRII patients with LE-DVT.
In conclusion, the incidence of LE-DVT was 5.3% in CRII patients after pelvic malignancy radiation, and recent surgical history, and reduced Hb levels were independent risk factors, which could potentially be diagnostic markers for predicting the presence of LE-DVT in CRII patients. When the Hb lower than 82.5 g/L in CRIIpatients or/and recent surgical history shorter than six months, it is necessary to note whether there is LE-DVT or noteven if no suspicious symptoms of LE-DVT occurred. In addition, colostomy treatment might be a good choice for intractable hemorrhagic CRII patients with LE-DVT, in whom it was much safer to adopt anticoagulant therapy after colostomy, followed by obvious bleeding remission.