This literature review was performed by conducting a systematic search of PUBMED, MEDLINE, PMC, GOOGLE SEARCH including all articles up to February 2015. Keywords used for the search included ’radiation proctitis’, ’radiation proctopathy’, ’management of radiation proctitis’, or ’radiotherapy complications of pelvic malignancies’.

Details are given in [Table/Fig-1].

Radiation proctitis is a common complication following radiation therapy of pelvic malignancies, like malignancies of prostate, cervix, uterus, bladder, testicles, rectum and lymphomas [2]. Acute radiation proctitis occurs during or within three months of the radiotherapy treatment and are usually self limiting [1]. It is usually seen in about 13% of patients receiving radiotherapy, while 5-10% of patients develop chronic radiation proctitis [5]. Chronic Radiation Proctitis (CRP) either continues from the acute phase or begins after a latent period of at least 90 days. Chronic proctitis occurs generally in patients with severe acute proctitis and in those with predisposing conditions of diabetes mellitus, inflammatory bowel disease, hypertension, peripheral vascular disease, or even chemotherapy [1].

Tissue changes can occur early in the course of radiation therapy. The initial microscopic changes include mucosal cell loss and distortion of the vascular endothelial cells. Acute inflammation in the lamina propria, endothelial swelling in the arterioles and eosinophilic crypt abscess formation, are seen as the injury progresses [1,2]. Other changes include neovascularisation and dilatation of small vessels. Severely affected portions develop progressive fibrosis of connective tissue, arteriolar endarteritis and tissue ischaemia, leading to eventual mucosal friability, ulcers, strictures and fistulation [3,4].

The most common presenting symptoms are bleeding per rectum and intestinal obstruction from strictures and sepsis [1]. The rectum is commonly affected organ and the common site of injury following radiotherapy of the pelvic and perineal organs due to its relatively fixed central position in the pelvis. Acute radiation proctitis may present with mild diarrhoea, urgency, tenesmus, generally without rectal bleeding [2]. Chronic lesions are irreversible and progressive, and can lead to arteritis obliterans and interstitial fibrosis of the entire rectal wall [6]. The prognosis of radiation proctitis remains unclear. Though rarely life-threatening, radiation proctitis may eventually progress to become chronic with morbid sequelae including persistent bleeding, strictures and fistulae and rarely, carcinomatous change [7].

Management of patients with symptomatic radiation proctitis remains essentially empirical and is suitably individualized. There are a few randomized trials and no consistent guidelines for the treatment of radiation proctitis which have been put forward. In general, non-surgical interventions usually form the first line of treatment and surgery is reserved for the advanced or refractory cases [1,2].

Sulphasalazine, balsalazide and mesalazine are some of the anti-inflammatory drugs which have been tried in the treatment of radiation proctitis. The active component in these drugs is 5- Aminosalicylic acid (5-ASA) which probably decreases the severity of acute intestinal inflammation. The anti- inflammatory action is exhibited by varied mechanisms, which includes scavenging of oxygen radicals, inhibition of biosynthesis of prostaglandins, and alteration of bacterial flora [8]. In a case series of four patients, sulphasalazine showed improvement in symptoms [9]. The use of balsalazide in patients undergoing prostate cancer radiotherapy has shown to prevent the radiation proctitis and improve the toxicity grades. Balsalazide was administered as 2250 mg of dose, twice daily beginning 5 days before RT and continuing for 2 weeks after completion of the treatment [10]. Seo et al., treated 23 patients of radiation proctitis with oral and topical mesalazine combination therapy. There were improvements in the mean telangiectasia score and the bleeding score with the mesalazine [11]. Overall, the clinical evidence on the role of 5-ASA in the treatment of radiation proctitis is not sufficient to recommend the routine use in radiation injury [12].

Antioxidants are supposed to have cytoprotective effects to the intestinal tissue by reducing the cellular oxidative stress following radiation. Kennedy et al., has found a sustained therapeutic benefit with vitamin E and C in patients of chronic radiation proctitis [13]. In another trial by Ehrenpries et al., retinol palmitate significantly reduced rectal symptoms of radiation proctopathy [14]. Though, benefits seem to occur, more studies are required to establish it’s role in the current practice [12].

Sucralfate (aluminium sucrose octasulfate) is a sulphonated polysaccharide which adheres and thus, protects the mucosal cells. Other mechanisms responsible for its cytoprotective effects are stimulation of prostaglandin synthesis, increased local blood Flow and more local production of epidermal growth factor [15]. It is administered either by the oral route or as suspension enema. Sasai et al., has observed benefits with oral administration of sucralfate in the treatment of chronic radiation proctopathy [16]. Patients with refractory proctopathy were given oral sucralfate and after two months of the treatment, all three patients improved endoscopically and clinically. During a mean follow-up period of 3 years, none of them developed significant recurrent haemorrhage [16]. Sucralfate enemas are safe and well tolerated. Sucralfate enemas have been evaluated by Kochhar et al., in 26 patients. All were treated with 20 mL of 10% rectal sucralfate enemas [17]. Positive response was achieved in 20 patients at 4 weeks, 22 patients at 8 weeks and 24 patients (92.3%) at 16 weeks. No treatment-related complications were noted [17]. Sucralfate paste enemas have shown clinical improvement in 23 patients of chronic radiation proctitis, when given twice daily for two weeks [18]. Additional use of metronidazole may enhance this effect of sucralfate [19]. The use of sucralfate is not recommended in patients with acute proctitis as prophylactic treatment [20].

They have anti-inflammatory action and exert their effect by inhibiting the arachidonic acid cascade, inhibiting cytokine production, blocking histamine release and stabilizing cell membranes [2]. Sanguineti et al., conducted a study to find that hydrocortisone enema is not superior to sucralfate in preventing acute rectal toxicity [21]. At present, it is anticipitated that corticosteroid enemas have limited effects on chronic radiation proctopathy.

Formalin therapy is effective in about 48% of patients of chronic radiation proctitis [22,23]. Local instillation of formalin has shown good results in the management of haemorrhagic radiation proctitis [24]. In radiation proctitis, formalin helps to sclerose and seal the fragile neovasculature and has been widely used. Its success relies on the accurate localisation and application at all the affected areas [1]. Pironi et al., stated that the application of 4% formalin solution is an effective, safe, and well-tolerated treatment for chronic radiation-induced haemorrhagic proctitis with minimal discomfort and no severe complications [25].

Sodium butyrate enemas were found to alleviate acute symptoms in the cases with radiation proctitis, though there seems to be no effect on the incidence and severity of late proctitis [26]. In a recent study, Vernia et al., observed that on administering sodium butyrate enemas at a dose of 80ml/24h, remission in clinical symptoms of radiation proctitis can be achieved [27].

Hyperbaric oxygen is postulated to exert its therapeutic role in the treatment of CRP. This therapy reverses tissue hypoxia by inducing neovascularisation [28]. It also stimulates collagen formation and re-epithelialization [28]. HBOT successfully alleviated the symptoms in 89% of the patients with radiation proctitis. There were only trivial symptoms after HBOT in 22% of the patients. No severe side effects were observed and treatment compliance remained high [29].

Treatment with hyperbaric oxygen in chronic radiation proctitis has also shown promising results in a large randomized trial done on 120 patients. It has significantly improved the healing responses with better bowel-specific quality of life in patients with refractory radiation proctitis [30].

Treatment of radiation proctitis with pentoxifylline might have modest benefit when given for longer duration. Venkitaraman et al., have done a prospective randomised controlled study on 40 patients and could not show a statistically significant advantage with 6 months of pentoxifylline compared with standard measures for late radiation-induced rectal bleeding [31].

Rebamipide enema therapy for radiation proctitis is a safe and effective treatment when first treatment or other conservative management has failed. Kim et al., administer enemas containing 150 mg rebamipide per dosing after morning bowel movement, and always prior to bedtime, twice daily for 4 weeks. The mean improvement in bleeding point scores, friable mucosa scores and telangiectasia scores were all statistically significant and also no side effects were noted in any of the patients [32].

Retinol palmitate significantly reduces rectal symptoms of radiation proctopathy, most probably because of wound-healing effects. A study comparing retinol palmitate (10,000 IU per oral for three months) to placebo revealed that oral administration of retinol palmitate (vitamin A) is able to reduce radiation proctitis symptoms [33].

Pinto et al., conducted a prospective, randomized trial in which short chain fatty acid enemas were compared with placebo in 19 patients of chronic radiation proctopathy [34]. Patients were given daily enemas for five weeks and were subsequently followed up for 6 months. No statistically significant difference was noticed between the placebo and the treated group after six months of follow-up [2].

In a study, two patients of radiation proctopathy were treated for the complaint of bleeding with a combination of oestrogen/progesterone. Complete cessation of bleeding was seen in both the patients but they developed worsening cardiovascular disease [35].

In a study on sodium pentosan polysulphate, 13 patients of chronic radiation proctitis were taken and evaluated. Complete response was seen in nine patients (82%). Maculopapular rash during therapy was noticed in one patient [36].

Misoprostol promotes mucosal blood flow and acts as a cytoprotective agent. Khan et al., performed a prospective, randomized study to evaluate the role of misoprostol rectal suppositories in the prevention of radiation proctopathy. Misoprostol suppositories (made from two 200μg tablets) were given to the patients and symptom scores were found to be significantly lower than those in the placebo group [37].

Endoscopic therapies are considered as the treatment of choice in patients of chronic radition proctitis with troublesome bleeding. These may also be used along with medical therapies in treating the patients [12]. The goal of endoscopic therapy, is the obliteration of telangiectasias, regardless of methodology [2]. Options include contact methods, like the heater probe and bipolar electrocautery, and non-contact methods, such as laser therapy, argon plasma coagulation, radiofrequency ablation and cryotherapy [28]. It appears, however, that non-contact methods are better in comparison to thermal contact methods of endoscopic treatment. The methods like heater probe and bipolar electrocautery have reported higher incidence of bleeding as a side effect of the treatment and they also require significantly longer sessions of the endoscopic treatment.

The heater probe and bipolar electrocautery probe are the contact probes, and deliver the therapy directly to the site of active bleed [28]. The common disadvantage includes the formation of char on the tip of the probe which leads to decrease efficiency of the treatment and require repeated cleaning [28]. Eight patients were treated by Fuentes et al., with the heater probe for rectal bleeding. One to four treatment sessions were required for the symptomatic improvement in bleeding [38]. Jensen et al., treated 21 patients either by a bipolar electrocoagulation probe or a heater probe. Episodes of severe bleeding were significantly lesser with the heater probe (67% vs 11%) and bipolar probe (75% vs 33%) in comparison to the medical therapy [39].

The importance and use of endoscopic laser therapy in the treatment of chronic radiation proctitis was first described in 1982. The lasers are in common use and are effective in the treatment of chronic radiation proctopathy [2].

Nd:YAG laser was among the first endoscopic laser modalitiy used [28]. Nd:YAG laser is ideal for deeper vessel coagulation as it is well absorbed by tissue protein [40]. The wavelength used for the treatment is 1064nm and it penetrates to a depth of up to 5mm [28]. Complication rates are around 5-15% [2]. Stricture formation, transmural necrosis and recto-vaginal fistula are some of the complications seen [28]. Successful treatment of rectal bleeding was seen by Leuchter et al., in a patient after four applications [41]. The use of this laser for chronic radiation proctitis has declined due to its cost, the possibility of severe endoscopic damage and the need to aim directly and accurately at telangiectasias [28].

The beam from the Nd:YAG laser is passed through a KTP crystal and is then used as KTP laser. The wavelength of this laser is reduced by half (532 nm). The energy is absorbed at this wavelength by haemoglobin and thus, the depth of penetration is shallow (1-2 mm). Therefore, it is useful for treating superficial vascular lesions [28]. Twenty six patients of chronic radiation proctitis were treated with KTP laser and evaluated by Taylor et al. The treatment was given using 4-10 W and a median of two sessions. Symptomatic improvement was observed in 65% patients, while 30% of the patients have shown no response. No complications like fistula or perforations were reported [42].

The argon laser and KTP laser are functionally similar and have similar wavelength. The depth of tissue penetration is about 1-2 mm. Hence, it is also useful in blood vessel photocoagulation for superficial lesions [28]. The argon beam laser appears to be safer with less transmural inflammation, fibrosis, stricture formation [2]. O’Conner treated five patients and cessation of bleeding was seen after two to four sessions of the treatment. Argon laser at 1.5 W was used in the study. Each treatment session consisted of approximately 50 pulse where each pulse was applied to the telangiectatic lesions with direct circumferential contact [43]. Taylor et al., reported symptomatic control in 14 patients after a median of three sessions. Maintenance therapy was required in ten patients (71%) for recurrent bleeding approximately every 7 months [44].

Argon Plasma Coagulation (APC) uses inert argon gas as a conducting medium and bipolar diathermy current is delivered. Limited depth of coagulation (0.5-3mm), uniform and predictable application are some of the advantages seen with it’s use. The risks of perforation, stenosis and fistulisation are reduced. Another benefit is that, it can also be applied radially and axially, thus, allowing tangential coagulation of lesions [28]. In addition, as APC treatment is being delivered using the colonoscope, it can reach more proximally affected parts of the rectum [1]. Now-a-days, APC has rapidly become the preferred and first-line endoscopic therapy for haemorrhagic CRP [28].

It has been found that APC has the potential to complement topical formalin application and can be used in combination to treat the proximal and distal rectum concurrently. This series has also found that all the patients failed initial conservative management for per rectal bleeding, and should thus be either offered empirical treatment at the time of diagnosis with formalin or APC, or at least be followed up closely following a course of stool softeners and antibiotics such as metronidazole [1].

Most studies have shown benefit on using APC for the management of chronic radiation proctitis. Improvement in rectal symptoms like tenesmus, diarrhoea has been noticed in 60%-75% of the cases. APC also alleviates rectal bleeding in 80%-90% of the cases [28]. Multiple treatment sessions are required in the diffuse lesions, usually ranging from one to five sessions [28].

Hortelano et al., have recently analysed the response of APC in 30 patients of chronic radiation proctitis. Out of all, 77% patients demonstrated complete response while 16% patients revealed partial response. Transfusion was not required in any of the patients following therapy. Long-term (>6 weeks) grade 2 rectal ulceration and grade 2 rectal incontinence were seen in two patients [45].

Overall, the varied complication rates have been observed with the use of APC. Overall morbidity was reported in 47%, post-treatment pain in 20% and severe complications (severe bleeding, extensive necrosis and perforation) in 10% of the patients [28]. The commonest procedure-related complication observed is rectal or anal pain and it usually resolves spontaneously [28]. Rectal ulcers are common following APC treatment. Therefore, recommendation is to give brief pulse treatment to the lesions [46]. Occurrence of ulcers may be affected by the various factors, including the method of application, the time interval between the sessions of the treatment and the flow rate of the argon gas [47]. Rare complications reported include urinary retention, necrosis and arteriovenous fistula [28]. The occurrence of strictures is less common and varies among different studies, from 2%-13.3% [28].

Radiofrequency Ablation (RFA) is a possible treatment of radiation proctitis though the data confirming its role is scarce. RFA restricts the treatment to the superficial mucosa and the deep tissue injury is avoided especially in relatively ischemic mucosa and thus, the lesser risk of post-treatment ulceration and structuring. In comparison to the point-by-point approach as required with APC, heater or bipolar probes, RFA allows simultaneous treatment of much broader areas of tissue. It also leads to squamous re-epithelialization and thus prevents the rebleeding [28].

Zhou et al., have used RFA for treating three patients suffering from CRP. In all cases, the BARRx Halo90 system was used for the delivery of treatment and the procedure was tolerated well. Haemostasis was achieved effectively after one or two sessions of RFA. No ulceration or stricturing was seen after 19 months of follow-up after the treatment [48]. The BARRx unit was mobile. A consistent amount of energy was delivered to the surface by BARRx unit which minimizes the possibility of over-treatment that may lead to ulcerations or perforations [28].

In another study, RFA was used to treat another case with extensive proctitis that continued to bleed despite giving treatment with APC. Post first treatment session, no significant bleeding was reported. Also, the patient remained free of symptoms for a period of 6 months during follow-up [49].

Some recent studies have suggested that RFA may prove to be an effective alternative to other endoscopic therapies, especially APC. It’s effect was reported in the two cases of chronic radiation proctitis, one of whom was transfusion-dependent and was successfully treated with focal RFA. Subsequent to treatment, haematochezia was decreased significantly. In total, three to four sessions were required to eradicate the neovascular lesions [50]. Similarly, Dray et al., reported that with use of RFA, clinical symptoms were decreased significantly and haemoglobin concentration was increased, thus reducing the need for transfusions. After RFA, the concentration of haemoglobin was increased in all 17 patients during the follow-up period of 6 months [51].

Cryoablation is a procedure in which tissue destruction is done via application of extreme cold temperatures to the target. It has the advantage of uniform treatment of larger surface areas. The first case of successful use of low-pressure cryoablation in resolving the symptoms of radiation proctitis was reported by Shaib et al. Cryoablation therapy was administered using a liquid nitrogen spray which is injected through the cryoablation catheter. Each area of proctitis was treated by a total of four applications with each of 10s duration. No adverse effects after cryoablation were seen [52]. Battish et al., have shown similar results in a case series of two patients who underwent cryoablation using liquid nitrogen for the radiation proctitis. Each patient underwent 4 applications of 10 s each and complete resolution of mucosal bleeding and telangiectasias was noticed on the subsequent endoscopy [53].

Hou et al., have observed the benefit of using cryoablation therapy in a prospective study of 10 patients with haemorrhagic radiation proctitis. Mean follow-up in the study was 3.3months. All of the patients received a single session of cryotherapy. Each session consists of three applications of 5s each to each area of involved mucosa. There was a 37% decrease in the rectal telangiectasia density. Though, symptomatic improvement was observed in 80% of patients, endoscopic improvement was seen in 70% of the patients. Severe complication of cecal perforation was seen in one patient secondary to over- insufflations. One case (10%) of rectal ulcer was also observed [54].

Only a few studies have been reported using cryoablation in CRP and there has been no prospective study confirming and comparing the utility of cryoablation with other treatment modalities [28]. [Table/Fig-2,3] outlines the different modalities used for the treatment of radiation proctitis.

Mesenchymal Stem Cells (MSCs) are isolated from bone marrow. They are the pluripotent progenitor cells and play an important role in the maintenance and regeneration of various connective tissues [5]. MSC therapy is supposed to have role in extracellular matrix remodelling, proangiogenesis and inflammatory modulation. In a recent study by Linard et al., on pigs, autologous MSCs (2 × 106 MSCs per kilogram in sterile phosphate-buffered saline [PBS]) were given in the ear vein once a week on days 27, 34, and 41 postirradiation to assess the response in the radiation induced proctitis. In a pig model, repeated injections of MSCs have shown improvement in radiation induced fibrosis and inflammation. This therapy may be a light of hope to the patients suffering from severe proctitis and refractory to the nonsurgical interventions [5].

Fortunately, surgery is often a last resort to be used when severe complications occur, such as refractory bleeding, strictures leading to intestinal obstruction or sepsis. Surgery can range from a simple proximal diversion to a formal resection with or without an anastomosis [1]. It is noteworthy that all the patients who underwent an anterior resection with proximal diversions ultimately had their stomas reversed and there were no leaks thereafter. Thus, when appropriately indicated, surgery can offer an effective solution [1].

Many therapeutic agents ranging from oral drugs to the surgical interventions have been tried to control or alleviate the symptoms. Most of the studies pertaining to the treatment of chronic radiation proctitis are case studies or case series with a few randomized trials comparing the different modalities of the treatment. Non surgical interventions form the first line of treatment, especially endoscopic therapies. Now-a-days, APC has rapidly become the preferred and first-line endoscopic therapy. Surgery is reserved for the intractable symptoms or severe complications of radiation proctitis. Treatment with mesenchymal stem cell injections may prove beneficial in future. Though, different options are available, exact utility and superiority of one line of treatment over other is yet to be found.