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Introduction
Radiotherapy for treatment of genitourinary and lower gastrointestinal malignancies can cause damage to rectum including left colon. It commonly leads to acute radiation proctitis. If symptoms persist more than 3 months after finishing radiotherapy or develop later, it is chronic radiation proctitis (CRP). The term radiation proctitis can be misleading as the epithelial damage to the rectum is due to radiation with minimal inflammation and probably more appropriately called ‘chronic radiation proctopathy’1.
Cancers of the cervix, prostate, rectum, bladder, testicles, and uterus are commonly treated with pelvic irradiation. Among these prostate malignancy is the most frequent cause in western countries1. But in India cancer cervix is the commonest cause of CRP. Incidence of chronic radiation proctitis can be as high as 20 to 30%1,2.
The method of radiation delivery is an important predictor of the risk for radiation proctitis. The rate of colorectal complications with brachytherapy is lower compared to external beam radiation. The use of newer conformal radiation therapy techniques maximizes the dosage directed to the tumor while minimizing the dosage of radiation to the rectum1,2. CRP may be more frequent in patients with inflammatory bowel disease, diabetes, hypertension, or peripheral vascular disease and in those who develop severe acute proctitis1.
Diagnosis
CRP should be suspected in patients who develop symptoms such as diarrhea, urgency, tenesmus, or bleeding, usually 3 months or more after pelvic radiation3. Bleeding occurs due to rupture of radiation induced telangiectasias in friable, ischemic mucosa. It leads to anemia and need repeated blood transfusions. Diagnosis can be confirmed bysigmoidoscopy2. Endoscopic findings of CRP are mucosal pallor, telangiectasias, hemorrhage, edema, and friability. Less frequent findings are ulcers, strictures, and fistulas. Routine rectal biopsy is not necessary except to rule out other pathology like colitis, IBD or malignancy.
Acute Vs Chronic Radiation Proctitis
The diagnosis of radiation proctitis can be separated into two distinct categories, acute or chronic, based on the timing to the development of symptoms and they have different presenting symptoms, incidence, histopathological findings, and treatment approaches which are summarized in Table 1. Symptoms that develop within 3 months from the initiation of radiation are classified as acute while those developing after are chronic. Brisk acute injury can persist into a consequential late effect, or late proctitis can develop in the absence of acute proctitis after a latent period of months to years after initial exposure. The median time for the development of chronic symptoms after radiation treatment is between 8 to 13 months in many series1,4. Although, a few series do report a considerably longer latent period, with initial symptoms developing more than 30 years after completing radiation4. A key distinction between acute and late proctitis is the relative lack of inflammatory infiltrate in the latter. Therefore, the term “proctitis’ is misleading and better known as chronic radiation proctopathy. (Table 1)
Scoring
For diagnosis, assessment of severity, prognosis and response to treatment different scoring systems are followed. They are based on symptoms, endoscopic findings, or both. Two commonly used clinical grading systems are LENT-SOMA scale rectum (Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scales) and Modified Radiation Therapy Oncology Group rectal toxicity scale. (Table 2 and 3)
Management
Management of CRP is mostly conservative with surgical intervention needed for intractable bleeding, rectovaginal fistula, rectal/anal stricture, or perforation. Available management options are listed in table 4.
Medical Treatment
There is no treatment only with oral drugs. Different combination of topical and oral medications used effectively.
Sucralfate is a highly sulfated polyanionic disaccharide. This drug acts via two mechanisms. First, sucralfate mechanically protects the gastrointestinal mucosa by forming a protective coating. Second, it is thought to stimulate epithelial healing by increasing angiogenesis. Numerous studies have been performed using sucralfate in oral and endorectal topical preparation (Table 5)
Despite mixed results for the oral preparation, the endorectal topical preparation of sucralfate can be considered an effective medical therapy for radiation proctitis with minimal side effects. Patients should take sucralfate enema twice daily, prepared using sucralfate suspensions (1 Gm /10ml diluted with water) applied per rectal with large syringe.
Formalin Therapy
Topical formalin application has been successfully used in patients with hemorrhagic cystitis. Since Rubinstein reported in 1986 the first successful treatment using a rectal wash with formalin, many authors have published on the treatment of hemorrhagic CRP using this therapy. Formalin, an aldehyde, functions as a local sclerosant and causes chemical cauterization of neovascular telangiectasias which stops recurrent bleeding.
In an email survey of the American Society of Colon Rectal Surgeons, formalin therapy was found to be the most popular method to treat CRP. Of the 327 respondents, 85% favored to formalin, while 42% used APC. Only 25% of practitioners reported using sucralfate (more than one modality could be chosen). Success rates vary from 27% up to 100%1. Unfortunately, formalin therapy is yet to be standardized. It has been used in different concentrations(commonly used as 4% solution), in different ways like instillation in the rectum through flexible endoscope (avoiding contact with anoderm or skin), irrigation in small aliquots, or applying soaked pledgets of cotton throughproctoscope/rigid sigmoidoscope. Therapy can be repeated in interval of three weeks or more until rectal bleeding stops. It should be avoided in cases of large rectal ulcer or stricture.
Patel et al9, in a retrospective study, evaluated the combination of oral vitamin A with formalin application. The addition of vitamin A led to a significant decrease in the number of formalin sessions and a significantly shorter time for resolution. Supplementation with vitamin A also has a better success rate in controlling rectal bleeding than formalin alone (94% vs. 64%). Few recent series are in Table 6.
The advantages of formalin application include low cost, wide availability,and good efficacy in general. Despite this, complications have been reported, including chemical colitis, anorectal pain, anal and rectal strictures, rectal perforation, fissures, incontinence, and diarrhea2.
Bipolar Cautery and Heater Probe
Endoscopic thermal coagulation with bipolar cautery or heater probeiseffective to control bleeding in CRP. The Bipolar probes have pair of electrodes (negative and positive) at its end through which current is passed using the tissue as a conduction surface. Both devices are directed in the setting of active bleeding. They cause less tissue injury (in comparison to laser therapy), permit tangential application of cautery, and both are relatively inexpensive and widely accessible. The disadvantage of both methods is char formation on the tip of the probe, requiring catheter retrieval and repeated cleaning and heater probe can cause deep coagulation.
In a randomized prospective trial by Jensen et al16, 21 patients with bleeding CRP were followed for 12 months with medical management. Then 9 patients were treated with heater probe and 12 with bipolar (power of 10-15 W). Bleeding episodes were significantly reduced without a statistically significant difference between the methods. There was hematocrit improvement and no major complications noted.
Lenz et al17 compared BiCAP with APC in a prospective randomized trial. 15 patients in each arm, all with active bleeding, were randomly selected for one treatment modality and success was defined as eradication of all viable telangiectasias. Both treatments were found to be equally effective with only one failure per group, and no differences were observed in number of sessions or relapses. Bipolar cautery was associated with a relatively higher rate of complications than the argon plasma coagulation group.
Argon Plasma Coagulation
Argon plasma coagulation (APC) is a noncontact thermal method of coagulation and hemostasis. APC uses high-frequency energy transmitted to tissue by ionized gas forming an arc which breaks once the tissue is desiccated. The theoretic advantage is a uniform, more predictable and limited depth of coagulation (0.5-3 mm), which minimizes the risks of perforation, stenosis, and fistulization.
APC is more commonly used as the endoscopic treatment of radiation proctitis, with a recent review showing around 80% of all current endoscopic specific literature focused on APC18.
Complications are usually minor in 5% to 20% cases like pain, fever, and rectal ulcer but rarely it can cause serious complications like explosions, rectal necrosis, stricture1,4.
Laser Therapy
Lasers cause thermal destruction by tissue absorption of laser light and have been used to CRP in small retrospective series. The Nd: YAG laser and KTP lasers have been used to coagulate bleeding vessels in the gastrointestinal tract. Taylor et al24 used KTP laser for treating 26 patients with bleeding secondary to CRP using 410 W and a median of two sessions. They reported a symptomatic improvement in 65% patients while there was no change in 7 (30%), and symptom like hematochezia increased in 1 (5%)
Laser treatment has limitations compared to other endoscopic interventions due to its high cost and inability to control the depth of penetration, which may increase risk of transmural necrosis, perforation, and fistulas. Therefore, its use in CRP has declined.
Radiofrequency Ablation
In Radiofrequency ablation (RFA) a needle electrode is used to transmit an alternating radiofrequency current into the tissue. At tissue temperaturesabove 60, the cell necrosis occurs. RFA is restricted to superficial tissue only avoiding deep tissue injury in ischemic mucosa. So,complications like deep ulceration and stricture formation rare and it allows re-epithelization.
There are few small studies with this technique, but the largest study on RFA was reported by Rustagi et al25, it included 39 patients. All experienced complete resolution of rectal bleeding after a mean follow up of 28 months. The common side effects were mild to moderate anorectal pain, temporary fecal incontinence, and perianal ulceration. However, despite these theoretical advantages, there are some limitations. These studies were retrospective, and conclusions are limited by the lack of a control group. They were also non-powered and even considering all published works, only a few dozen patients with CRP have been treated with RFA. Another important limitation is that no sigmoid or proximal rectal lesions were ablated, thus safety in those areas (with a thinner wall) remains uncertain. The cost of the RFA energy generator (applicable in only a few indications) and the price of the Halo catheter can be another drawback. Therefore, additional controlled studies are required to compare RFA to other therapeutic modalities for CRP.
Hyperbaric Oxygen Therapy
Hyperbaric oxygen (HBO) therapy enhances the innate healing abilities of a person through the inhalation of 100% oxygen, delivered in daily fractions over a period of weeks via a full body chamber with increased atmospheric pressure. HBO induces the regrowth of damaged vascular endothelial cells in marginally perfused tissue, improves the activity of antioxidant enzymes thereby reducing free radical damage, inhibit bacterial overgrowth and toxin production.
Side effects of HBO are mild like anxiety, otic barotraumas but need repeated sessions, efficacy questionable and costly. Though it can be considered as a treatment modality over more invasive procedures, it is not widely available or accepted.
Surgical Therapy
Surgical interventions should be reserved for those patients with either symptoms refractory to endoscopic therapy or for patients with complications such as brisk hemorrhage, perforation, fistula, or obstructing stricture. The need for such intervention is quite rare, in less than 10% of all patients with radiation proctitis4. Surgical options are diversion, reconstruction, or excision like proctectomy or pelvic exenteration.
Diverting stoma improves symptoms such as pain, tenesmus, drainage, infection and help in incontinence or stricture. Though a small study by Ayerdi et al29 showed improvement of rectal bleeding, usually fecal diversion has limited role in bleeding radiation proctitis. Fecal diversion like temporary colostomy is also required for management of strictures and fistula. Quality of life before and after diversion was studies in several reports. Pricolo et al30 reported a 30 year review of the experience at a single institution including 60 patients treated with diverting ostomy in addition to other surgical approaches. Quality of life was examined and for some patients a diversion was so effective additional intervention was no longer needed.
Local excision with reconstruction by well vascularised advancement flap is used for fistulas or strictures. Proctectomy or pelvic exenteration is the most definitive as well as most extreme intervention. It should be offered only in cases of failure of other intervention to control bleeding, intractable pain, or fecal incontinence.
Discussion
Chronic hemorrhagic radiation proctitis is a difficult problem. Prevention can be ideal. Newer conformal radiation therapy techniques include intensity-modulated radiationtherapy and intensity-guided radiation therapies minimize the dose of radiation tothe rectum while maximizing dose to the tumor.Amifostine is a prodrug that is metabolized to a thiol metabolite whichscavenges harmful reactive oxygen species. When administered intravenously, it has shownsome benefit in preventing symptoms of acuteproctitis as well as decreasing the severity of chronic proctitis symptoms1,4. But toxicity of Amifostine, particularly hypotension, limits its routine use for prevention of late radiation proctitis. Sucralfate is extensively used for prophylaxis against acute radiation injury. However, placebo-controlled phase III trials have detected no benefit from either topical or oralsucralfate.
Despite there are many options of treating CRP still we don’t have clear recommendations or guidelines for management. Lack of detailed account of diagnosis, background co-morbidities, accepted clinical / endoscopic scoring system and outcome of treatment are the limitations. We need many more randomized data with head-to-head comparative studies for guiding protocol.
Few headtohead comparative trials have been performed on different treatment methods for radiation proctitis. Two important studies comparing between APC and formalin which are commonly used. First, a study by Alfadhli et al19 retrospectively compared outcomes for 22 patients who were treated with APC alone (n = 11), formalin instillation alone (n = 8) or both (n = 3). Patients treated with APC had a significantly improved chance for control of rectal bleeding while those treated with formalin had an increased likelihood of adverse events including nausea, vomiting, cramps and rectal pain. The second study, by Yeoh et al22, reported on 30 men with intractable chronic proctitis after receiving radiation for prostate cancer. All men were randomized to APC or topical formalin. Reduction in rectal bleeding was achieved in 94% of the APC group and 100% of the formalin group after a median of 2 sessions in either arm. There were no differences between side effects of the two treatment modalities.
Based on the available evidence it can be concluded that management of CRP should be a ‘step-up’ approach. Many of the patients can be managed effectively at home with sucralfate enema with or without metronidazole, which is cheap, effective and without toxicity. More severe disease or patients not responding to sucralfate enema should be treated with 4% formalin instillation or APC. Between these two, 4% formalin is cheap, easily prepared and preferably should be given in low dose contact instillation through proctoscope or sigmoidoscope to limit toxicity. Argon plasma coagulation is effective but costly and need endoscopic expertise. APC may be a better option in cases of radiation colitis. These two endoscopic methods should be complementary. Hyperbaric oxygen therapy is difficult option in our country, but RFA may be a promising method considering its effect on re- epithelization in radiated tissue. Surgery is mostly needed for stricture, fistula, life-threatening bleeding but many times diverting stoma can improve patients’ quality of life.
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