DOI:http://dx.doi.org/10.7314/APJCP.2016.17.2.631 Novel and Effective Almagate Enema for Hemorrhagic Chronic Radiation Proctitis and its Risk Factors RESEARCH ARTICLE Novel and Effective Almagate Enema for Hemorrhagic Chronic Radiation Proctitis and Risk Factors for Fistula Development Zi-Xu Yuan1,2,3&, Teng-Hui Ma1&, Qing-Hua Zhong1, Huai-Ming Wang1, Xi-Hu Yu 1,3, Qi-Yuan Qin1, Li-Li Chu1, Lei Wang1,3*, Jian-Ping Wang1,3* Abstract Radiation proctitis is a common complication after radiotherapy for pelvic malignant tumors. This study was conducted to assess the efficacy of novel almagate enemas in hemorrhagic chronic radiation proctitis (CRP) and evaluate risk factors related to rectal deep ulcer or fistula secondary to CRP. All patients underwent a colonoscopy to confirm the diagnosis of CRP and symptoms were graded. Typical endoscopic and pathological images, risk factors, and quality of life were also recorded. A total of 59 patients were enrolled. Gynecological cancers composed 93.1% of the primary malignancies. Complete or obvious reduction of bleeding was observed in 90% (53/59) patients after almagate enema. The mean score of bleeding improved from 2.17 to 0.83 (P<0.001) after the enemas. The mean response time was 12 days. No adverse effects were found. Moreover, long-term successful rate in controlling bleeding was 69% and the quality of life was dramatically improved (P=0.001). The efficacy was equivalent to rectal sucralfate, but the almagate with its antacid properties acted more rapidly than sucralfate. Furthermore, we firstly found that moderate to severe anemia was the risk factor of CRP patients who developed rectal deep ulcer or fistulas P( = 0.015). We also found abnormal hyaline-like thick wall vessels, which revealed endarteritis obliterans and the fibrosis underlying this disease. These findings indicate that almagate enema is a novel effective, rapid and well-tolerated method for hemorrhagic CRP. Moderate to severe anemia is a risk factor for deep ulceration or fistula. Keywords: Chronic radiation proctitis - hemorrhage - almagate - risk factor - rectal fistula - enema. Asian Pac J Cancer Prev, 17 (2), 631-638 Introduction endoscopic argon plasma coagulation (APC) (Postgate et al., 2007), hyperbaric oxygen (Charneau et al., 1991), Radiation proctitis is a common complication after topical formalin application (Patel et al., 2009). Surgical radiotherapy for pelvic malignant tumors, for the fixed intervention is often reserved for refractory bleeding location of the rectum and anatomic relationship with or complications like fistula and stricture. And the other organs (Wang et al., 1998). Acute radiation-induced reported procedures included diversion colostomy and injury that occurred during radiotherapy is often self- proctectomy (Anseline et al., 1981; Khubchandani et al., limiting and easy-cured. The chronic modality that can be 1987; Lucarotti et al., 1991; Nowacki, 1991). The results delayed from months to years after radiation treatment, of these methods are variable and the overall efficacy has accounted for 5% to 20% of the cases (Pesee et al., been unsatisfactory (Kim et al., 2008). 2010). Chronic radiation proctitis (CRP) is difficult to This study was to introduce a novel agent of rectal manage for recurrent rectal bleeding and required blood almagate (aluminium-magnesium hydroxycarbonate transfusion in severe cases (Haas et al., 2007; Leiper and hydrate, an antacid agent) enema and evaluate its short- Morris, 2007; Patel et al., 2009). There are no well-defined and long-term efficacies for hemorrhagic CRP in our guidelines for the management of CRP. Various medical center. Furthermore, we performed analysis of potential agents for CRP have been reported , including sucralfate risk factors for rectal fistula in CRP patients. (Kochhar et al., 1988; R et al., 1991), 5-aminosalicylic acid analogue sulfasalazine (R et al., 1991), corticosteroids (R Materials and Methods et al., 1991), metronidazole (Eaveiæ, 2000), rebampide (Kim et al., 2008), short-chain fatty acid (Talley et al., Patients 1997), vitamin A (Patel et al., 2009) and pentoxifylline Patients with hemorrhagic CRP treated by (Hille et al., 2005). Other treatment modalities included hospitalization at the Sixth Affiliated Hospital of Sun 1Department of Colorectal Surgery, 3Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA &Equal contributors *For correspondence: Lei Wang ([email protected] or wangl9@mail. sysu.edu.cn), Jianping Wang ([email protected]) Asian Pacific Journal of Cancer Prevention, Vol 17, 2016 631 Zi-Xu Yuan et al Yat-Sen University were evaluated from 2007 to 2015. All social); three scales of symptoms (pain, fatigue, and patients underwent flexible colonoscopy before enema to nausea/vomiting); and one global health and quality of confirm the diagnosis of CRP. This study was approved life scale. Six single-item symptom measures (dyspnea, by the ethics committee of the Sixth Affiliated Hospital of insomnia, appetite loss, constipation, diarrhea, and Sun Yat-Sen University and was in accordance with the financial difficulties) were also included. provisions of the World Medical Association’s Declaration of Helsinki in 1995 (as revised in Tokyo 2004). Due to Risk factors the retrospective nature of the study, the informed consent Referring to the studies conducted by Li et al (Yang was waived. and Lv, 2012; Li et al., 2013), demographic and clinical variables which may affect the progression of CRP and Inclusion and exclusion criteria thus be possibly related to rectal deep ulcer or fistula CRP patients initially treated with rectal almagate (ulcer: ≥3 grades in VRS ) were evaluated: age; cumulative enema were enrolled. Patients with recurrent primary radiation dosage; presence of acute radiation-induced malignancies and had CRP less than 3 months after end enteritis; concomitant chemotherapy; latency of CRP; of pelvic radiation were excluded. These patients who duration of symptom; hypertension, diabetes mellitus were treated with almagate enema for less than one week and previous transfusion requirement; gynecological were also excluded. malignancy; CTCAE grades of bleeding; operations for primary tumors; body mass index (BMI); preoperative Grades and scores anemia; preoperative albumin and total protein in blood; Symptoms related to CRP, including rectal bleeding and APTT (activated partial thromboplastin time); and SCC other common concomitant symptoms such as anorectal (squamous cell carcinoma antigen) were also included in pain, tenesmus, stool frequencies, were graded before and the analysis of risk factors. after enema according to Common Terminology Criteria for Adverse Events (CTCAE) (CTCAE 4.0 – June 14, Statistical analysis 2010, National Institutes of Health). Typical endoscopic Statistical analysis was performed with SPSS version photos and pathological representative images were 13.0 software (IBM, USA). Continuous variables were collected to present the classical features of CRP. The analyzed by Student’s t test, and categorical variables were severity of endoscopic bleeding was scored according to compared by the Pearson Chi-square test. Parametric test - the endoscopic Vienna Rectoscopy Score (VRS) systems Wilcoxon rank sum test was performed to compare ranked (Wachter et al., 2000). Briefly, VRS contains five common data such as CTC grades of symptoms, VRS grades of endoscopic findings of CRP, i.e., telangiectasia, congested endoscopic findings, and the quality of life. Potential risk mucosa, ulceration, stricture, and necrosis. factors related to rectal fistula were evaluated by univariate analysis. Multivariate logistic regression analysis was not Almagate retention enema conducted because only one variable of moderate to severe Enemas were prepared by diluting 15 ml of almagate anemia with a P value less than 0.1. All P values were suspension (1.5 g) in 30-50ml normal saline. Almagate two-sided and less than 0.05 were considered statistically enemas were administrated through the anal via a soft significant. suction tube inserted 5-8cm into the anal verge twice daily at wards. Enemas were tried to retain in the rectum Results for about 60 min with intermittent position change from left lateral to supine and to right lateral every 20 minutes. Patients’ democraphics Since no previous experience of almagate enema existed, A total of fifty-nine patients treated for hemorrhagic patients were usually discharged upon the cessation or CRP at a single center were analyzed. Demographic and obvious reduction of rectal bleeding when it was possible clinical data were collected (Table 1). Gynecological and safe to continue enemas by self-administration at cancers composed 93.1% (55/59) of primary malignancies. home. Response was defined as a 0 or 1 grade of bleeding The mean radiation dosage was 82.5 Gy (range: 40-120 after enema. In those patients with poor response at Gy, defined as the cumulative dosage of external and 2 weeks, or requiring blood transfusion again were endocavitary radiation, and included the radiation for considered to be failed. both the site of primary malignancy and metastatic lymph nodes). The onset of symptoms occurred at a mean 9.3 Follow-up (range: 0-36) months after radiotherapy. Mean VRS was A long-term follow-up was done by a telephonic 3.9 points. questionnaire or by searching medical