Clinical features, outcome and risk factors in cervical cancer patients after surgery for chronic radiation enteropathy

Because the management of cervical cancer is stratified by tumour stage, we undertook this retrospective study to analyse the clinical characteristics and postoperative outcomes for inpatients with CRE requiring surgery after RRT or RS plus RT. In this series of 166 consecutive cases of CRE requiring surgery, more patients suffered from radiation-induced fistula, perforation and proctitis in the RRT group. An aggressive intestinal resection procedure was performed in almost all of the cases with overall and major morbidity rates of 63.9 % and 14.5 %, respectively. Although the surgical procedure is very difficult in patients with CRE, extensive resection of irradiated bowel is suitable and feasible with acceptable postoperative outcomes.

Radiation induced digestive stenosis, which was responsible for complete or incomplete obstruction, was the most common symptom and surgical indication (81.9 %); this finding is consistent with the previous literature [21‐23]. Concerning the site of obstruction, our results indicated that the terminal ileum/ileocecum was the most frequently and severely affected site. Several studies have also reported similar results [23, 17]. Iraha et al. [17] reported that 37 out of 48 gynaecological cancer patients developed radiation induced stenosis requiring surgical management, and found that the terminal ileum, sigmoid and rectum were the sites of the majority of the radiation-induced lesions. The current case series revealed that the incidence of radiation-induced stenosis in the RS + RT group was higher than in the RRT group (90.8 vs 65.2 %; p = 0.000). A possible explanation for the increased incidence of obstruction could be the gynaecological surgical procedure for cervical cancer, during which surgical extirpation of the uterus or other organs allowed normal bowel fall within the pelvic radiation field [17]. In addition, postoperative adhesion can affect the normal mobilization of the intestine, which causes the small bowel loops to be fixed in the pelvis. The fact that the intestine is more sensitive to radiotherapy and the presence of an impaired vascular supply resulting from the surgical procedure might have aggravated the damage to the irradiated intestinal.

Fistula and SCRP are probably the most severe and feared late toxicities following RT. As a result of symptoms including leaking urine or stools, persistent bleeding, vulnerability to infection and unbearable pain, patients may suffer significant physical, social and psychological distress which negatively impacts on their quality of life [24, 25]. The incidence of radiation-induced fistulas was estimated as between 1 % and 4 % for all-comers, while this number can be as high as 22–48 % for more advanced stages, which is similar to our findings [24, 26]. In the current series, the incidence of fistula and SCRP (as the main symptoms of patients who underwent surgery) in the RRT group was significantly higher than that in the RS + RT group (17.4 % vs 5.8 % [p = 0.020] and 10.9 % vs 1.7 % [p = 0.027], respectively). The probable reason was that most patients in the RRT group had advanced stage disease and received a higher cumulative radiation dose, which correlated closely with an increased incidence of late toxicities following RT. Correlations between the radiation dose and the incidence of sequelae have been reported by many authors [27, 28]. In a review of 1456 patients with cervical carcinoma (stages IB–IVA) treated with RT (70–90 Gy), Perez et al. [28] quantified the impact of various dosimetric parameters on the incidence of significant morbidity. They observed an incidence of recto-sigmoid morbidity of < 4 % with doses below 75 Gy and 9 % with higher doses; for the small intestine the incidence of morbidity was < 1 % after a total dose of ≤50 Gy, 2 % after 50–60 Gy and 5 % after higher doses. Previous series have noted a variety of risk factors for severe late toxicities, but common predictors tend to include advancing tumour stage, previous pelvic radiotherapy, the use of RS, an active smoking habit and elevated RT doses [29, 11, 26]. The poor wound-healing characteristics that increase susceptibility to fistula development can largely be attributed to sclerosis in small and medium sized blood vessels, relative tissue hypoxia and soft tissue fibrosis that occurs following RT [25].

Most patients with refractory complications had more than one radiation-induced late toxicity, which increased the complexity of the disease [30]. In the current study, 42 patients underwent both ileal/ileocecal resection and stromal diversion because of radiation-induced multiple injuries. Turina et al. [30] also reported that over two-thirds of their patients developed two or more complications from RT, and many patients required a major operation with faecal diversion and subsequent restorative operations as a result of the severity of the RT injuries.

Although not statistically significant, the incidence of perforation in the RRT group observed in the present series was five times higher than that in the RS + RT group (6.5 % vs 1.7 %; p = 0.258); this was probably caused by the limited number of patients in the present study. We observed that the perforation site was the ileum in all five cases with abdominal pain as the prominent complaint, while only one (20 %) patient showed signs of acute peritonitis on physical examination. Yamashita et al. [31] also reported seven cases of small bowel perforation without tumour recurrence after pelvic radiotherapy for cervical cancer, and found that signs of peritonitis were absent in six (86 %) cases with severe abdominal pain as the main complaint. The absence of signs of acute peritonitis might have been attributable to the nature of its histopathological features, including obliterative endarteritis and progressive stromal fibrosis in the submucosal/subserosal layers, which limited inflammation resulting from severe abdominal adhesion.

Optimal surgical strategies for patients with CRE remain controversial. Various surgical procedures have been proposed, including aggressive resection/anastomosis, adhesiolysis, stoma formation and bypass. According to the experience from our centre and others [16, 32, 17, 12], the optimal procedure for CRE is resection and anastomosis, and the avoidance of bypass or other conservative procedures. If there is severe dense adhesion or poor general condition, a conservative procedure could be considered as an alternative option. Aggressive resection of the radiation-induced lesions, if possible, would improve the long-term outcomes after surgery. Lefevre et al. [21] demonstrated the importance of resecting all damaged tissue in patients with CRE, and reported that as compared with bypass or adhesiolysis, ileocecal resection was the only factor that protected against reoperation for recurrence.

In the present study, 140 (84.6 %) patients received an aggressive resection procedure (57.8 % with anastomosis and 26.5 % with ileostomy/colostomy) with surgical complications in 16.3 % and reoperation in 4.2 % of patients.

Overall and major postoperative morbidity, mortality and the incidence of reoperation in the two groups did not differ significantly. According to the updated Clavien–Dindo classification [20], overall postoperative morbidity and major (grades III–V) morbidity were observed in 63.8 % and 14.5 % of patients, respectively. Postoperative mortality was 2.4 % and incidence of reoperation was 4.8 %, which is comparable or lower than in previous reported series [33, 21]. Lefevre et al. [21] analysed 107 patients after extensive resection surgery for CRE and reported that the overall morbidity, surgical morbidity and postoperative mortality were 74.8 %, 28.0 % and 0.9 %, respectively. An earlier study by Regimbeau et al. [33] reported that postoperative surgical complications and mortality were 29 % and 5 %, respectively; anastomotic leakage occurred in 9 % of patients after aggressive surgery for CRE. Most patients in the present study experienced a planned procedure and nutritional support before surgery; this might have partly contributed to the decreased postoperative morbidity. In addition, nearly two-thirds of patients were operated in recent three years and given a targeted intervention following a detailed clinical algorithm, which could also have effectively improved outcomes.

During follow-up, mortality in the RRT group was significantly higher than that in the RS + RT group; seven patients died of MODS caused by intra-abdominal leakage or sepsis and four as a result of tumour recurrence. Of note, death secondary to postoperative complications usually occurred within 3 months after discharge, while patients with tumour recurrence tend to died 1 year later. Therefore, we believed that the focus should be on postoperative complications during the first 3 months after treatment, and then be transferred to tumour monitoring. In addition, the high incidence of permanent stoma in the RRT group might be demonstrated by the higher incidence of fistula and SCRP as a result of escalation of the radiation dose and advanced tumour stage. Because a fistula occurring in irradiated tissue can rarely be successfully repaired, most surgical treatments are palliative in the form of faecal or urinary diversion, leaving patients with a permanent colostomy or ileostomy [25].

The current study also analysed the risk factors associated with overall and major postoperative morbidity. In particular, severe intraperitoneal adhesion was significantly associated with major morbidity, which has also been identified in various previous studies [34, 35]. RT delivered to the pelvic/abdominal region could contribute to the formation of adhesions and fibrosis, perhaps as a result of vascular damage, which could cause stenosis, fistula and even death [35]. Furthermore, adhesions make subsequently intraperitoneal operations more difficult, and put the patient at higher risk for complications, such as enterotomy, fistula or injury to other intraperitoneal organs.

In multivariate analysis, preoperative anaemia was found to contribute significantly to overall postoperative morbidity, while ASA grades III–V, severe intraperitoneal adhesion and RTOG/EORTC grade V morbidity were significantly associated with major morbidity. Other predisposing factors associated with postoperative morbidity include diabetes mellitus, smoking, hypertension, previous abdominal surgery, concurrent chemotherapy and cumulative dosage, which have been reported in previously studies; however, we did not identify a significant correlation between these parameters and morbidity, probably because the limited number of patients enrolled in our study.

The present study had a number of limitations beyond its retrospective bias. It involved a single-institution sample at a tertiary-care referral centre. The true prevalence of CRE requiring surgery in cervical cancer patients remains unknown because of the paucity of prospective population studies. In addition, patients in the RRT group tended to be older, in worse condition and necessitated a far higher total radiation dose, which could be a confounding factor. However, the key objective of our study was to analyse the characteristics of CRE patients after they had received two treatment modalities (RRT vs RS + RT) for cervical cancer. The study was not novel but is of clinical importance and interest for clinicians regarding the evaluation of the disease course and prognosis.