Management of radiation-induced proctitis

A may occur during or shortly after radiotherapy to malignancies of pelvic and abdominal organs (1,2). This injury is usually self-limited (3-5). Clinical features of chronic injury may appear, however, from a few months to many years after radiotherapy (6,7). This chronic injury is not reversible, and rectal bleeding, tenesmus and diarrhea are the main symptoms. The incidence of serious injury rises sharply following a total radiation dose exceeding 50 Gy (8). The dose per fraction, however, is considered to be a more important factor of injury than total dose (9). Careful monitoring of the dose rate and its delivery in small fractions at specified intervals remains the most reliable way to reduce intestinal complications (8). Treatment of radiation proctitis is difficult, and nonsurgical therapy is the treatment of choice whenever possible because of high postoperative morbidity and mortality (10-12). In general, surgical intervention is necessary when it is complicated with perforation, obstruction, rectovaginal fistulas, or in intractable proctitis (7). This brief review will focus only on the conservative therapies.

This chronic injury is not reversible, and rectal bleeding, tenesmus and diarrhea are the main symptoms.
The incidence of serious injury rises sharply following a total radiation dose exceeding 50 Gy (8).The dose per fraction, however, is considered to be a more important factor of injury than total dose (9).Careful monitoring of the dose rate and its delivery in small fractions at specified intervals remains the most reliable way to reduce intestinal complications (8).
Treatment of radiation proctitis is difficult, and nonsurgical therapy is the treatment of choice whenever possible because of high postoperative morbidity and mortality (10)(11)(12).In general, surgical intervention is necessary when it is complicated with perforation, obstruction, rectovaginal fistulas, or in intractable proctitis (7).This brief review will focus only on the conservative therapies.

STEROID ENEMAS AND SUCRALFATE ENEMAS
Steroid enemas plus oral sulfasalazine have been recommended for radiation proctitis (13,14).The efficacy of the therapy, however, has been quite variable (15)(16)(17).On the other hand, some studies have also shown that sucralfate enemas are effective (18,19), even for patients who failed to respond to steroid enemas plus oral sulfasalazine (2,19).As a locally acting anti-ulcer agent with a generalized gastric cytoprotective effect, sucralfate binds to the defective mucosa and forms a protective barrier at the ulcer site.Its cytoprotective activity is through enhancing natural mucosal defence mechanisms by stimulation of gastric mucus secretion, epithelial cell renewal, endogenous prostaglandins production and mucosal bloodflow (20-22).
In the only available controlled trial, the efficacy of rectal sucralfate (2 g sucralfate in 10% suspension in water twice a day) plus tablet placebo (group 1) and steroid enemas (prednisolone retention enema 20 mg every 12 h) plus oral sulfasalazine (group 2) was compared (15).After four weeks of treatment, 16 of 17 patients (94.1%) in group 1, and eight of 15 patients (53.3%) in group 2 had clinically improved (P<0.001 and P<0.01, respectively).Endoscopically, 12 patients (70.6%) in group 1 and seven patients (46.7%) in group 2 had improved (P<0.001 and P<0.01, respectively).Both treatments have been reported to be effective, but better results were obtained from group 1.In addition, side effects (myalgia, nausea and headache) occurred in two patients in group 2 versus none in group 1.
In this prospective, randomized, double-blind controlled trial, however, the comparison was only between these two therapies.No placebo-controlled trials are available yet for further evaluation.Long term follow-up studies are required and different dosages of sucralfate need to be studied.
Hydrocortisone acetate is a rectal steroid delivering 80 mg hydrocortisone per dose.It exerts its action via a local anti-inflammatory effect of hydrocortisone on the mucosa.Eleven patients in our study with hemorrhagic radiation proctitis were treated either with hydrocortisone acetate alone or in combination with rectal 5aminosalicylic acid (5-ASA) preparations.All patients had rectal bleeding and diarrhea, and three had mild tenesmus before treatment.After one month of treatment, three of six patients (50%) treated with hydrocortisone acetate alone and three of five patients (60%) treated with the combination had clinically improved with either cessation or reduction of rectal bleeding, diarrhea and endoscopic improvement.No complications were noted.This limited observation may indicate that hydrocortisone acetate, either as a single agent or in combination with rectal 5-ASA preparations, can be beneficial for radiation proctitis.The value of hydrocortisone acetate and 5-ASA enemas needs to be evaluated in controlled studies.5-ASA enemas alone or with oral sulfasalazine were previously reported to be ineffective for chronic radiation proctitis in a small study (3).
Absorption of hydrocortisone acetate may be related to the degree of inflammation present.The foam preparation has advantages over liquid preparations: it is easier to retain, particularly in patients with urgency and tenesmus.It might also allow better coating of the inflamed mucosa.Because the affected area in radiation proctitis is usually a very short segment, the foam preparation probably delivers a higher steroid concentration to the affected mucosa because it does not disperse as widely as the liquid retention enemas.

5-ASA ENEMAS
5-ASA enemas have been reported to be ineffective for chronic radiation proctitis in a small study.The failure to respond to 5-ASA enemas is generally attributed to the late histological changes where a vascular-ischemic pathogenesis of radiation proctitis is present, rather than an inflammatory response (3).
Advanced proctitis was noted in all four patients in this study.The response to 5-ASA enemas in an earlier stage of the disease or as a protective agent during x-ray therapy during free radical injury, however, needs to be determined (8).5-ASA probably acts via anti-inflammation by interference with metabolism of either leukotriene A 4 or prostaglandins, altered immu- noregulation, oxygen radical scavengers and bacteriostatic function.

LASER THERAPY
Laser therapy applied in bleeding radiation proctosigmoiditis dates back to 1982 (23).Promising results have been continually reported thereafter.Most patients had been unsuccessfully treated with steroid enemas, sucralfate enemas and sulfasalazine in these studies (5,16,24,25).A long term study from an analysis of 14 patients for an average of 35 follow-up months (range two to 100) demonstrated that argon laser therapy is safe and effective for chronic radiation proctitis (26).In this study, a median of two laser treatments were required to control the initial bleeding; all patients improved or stopped bleeding within five days of treatment.Ten of 14 patients (71%) required maintenance therapy for recurrent bleeding.The intervals between maintenance treatments averaged seven months (range one to 36) and increased with time.Except for some bloating and minor cramping during treatment and for 1 to 2 h afterward, no other complications occurred in the follow-up period.
Argon laser therapy is theoretically advantageous over ND:YAG laser therapy.Its energy penetrates only 1 mm and is selectively absorbed by hemoglobin.In contrast, ND:YAG laser energy penetrates 3 to 5 mm and is nonspecifically absorbed by tissue proteins.This may result in transmural necrosis and fibrosis with perforation or stricture formation (26).A long term follow-up of eight patients (up to 60 months, average 21.7 months) has shown, however, that ND:YAG laser therapy is also effective and safe, although prolonged ileus and abdominal pain as complications (four episodes in 26 laser treatments) were observed (24).Laser therapy may cause bowel perforation.In addition, the endoscope may be prevented from reaching proximal bleeding sites if a radiationinduced stricture is present.Also, factors such as cost, facilities and special training staff should be taken into consideration.Repeated treatment may be required if bleeding recurs because of progressive formation of neovascular lesions (26).

FORMALIN TREATMENT
Formalin treatment of severe rectal bleeding from radiation proctitis was first reported in 1986 (27).Formalin treatment has recently been applied to a group of eight patients with hemorrhagic radiation proctitis, seven of whom stopped bleeding immediately after formalin application (28).No patient had recurrent bleeding for an average of four months of follow-up (range one to six months) and none required further blood transfusion after the treatment.These patients had previously failed on various therapies such as steroid enemas, sucralfate enemas, salazosulfapyridine and colostomy.Another two patients have been reported to have excellent responses (29).This therapy was accomplished by introduction of a rigid sigmoidoscope; bleeding surface was touched with a gauze soaked in 4% formalin until bleeding ceased (usually 2 to 3 mins).Formalin treatment can be repeated until bleeding is controlled (27).patient had recurrent bleeding for an average of four months of follow-up (range one to six months) and none required further blood transfusion after the treatment.These patients had previously failed on various therapies such as steroid enemas, sucralfate enemas, salazosulfapyridine and colostomy.Another two patients have been reported to have excellent responses (29).This therapy was accomplished by introduction of a rigid sigmoidoscope; bleeding surface was touched with a gauze soaked in 4% formalin until bleeding ceased (usually 2 to 3 mins).Formalin treatment can be repeated until bleeding is controlled (27).
Formalin treatment is reported to be simple, inexpensive and effective, but long term follow-up studies are needed.The proximal reflux of formalin and full-thickness damage of the bowel resulting from undue prolonged contact with formalin may occur as complications.If the concentration is less than 10% and the time of contact within 2 to 4 mins these complications can be greatly reduced (28).

HYPERBARIC OXYGEN
Severe bleeding from radiation proctitis was controlled with hyperbaric oxygen (HBO) in a patient who failed on laser therapy (12).The rectal bleeding decreased progressively after 15 days of HBO therapy.No rectal bleeding recurred four months after the treatment.The authors have proposed the therapy as an alternative to surgical treatment for this condition.Many treatments are necessary, however, for this therapy to be effective.HBO was delivered by a multiple chamber.The patient was treated at 2.533x10 5 Pa for 90 mins twice daily for a total of 123 h over 41 days.
HBO has been known for its treatment of severe radiation cystitis.The mechanism by which HBO affects radiation-induced proctitis is believed to be through promoting neovascularization and fibroblast proliferation, affecting red blood cells for oxygen transport and tissue exchanges, ameliorating hypoxia and enhancing white cell killing ability (12,30).

BIPOLAR ELECTROCOAGULATION
TREATMENT The idea of using bipolar electrocoagulation (BICAP) for radiation enteritis came from BICAP treatment of gastrointestinal bleeding angiomata.In a recent trial, four patients with radiation bowel injury were treated with BICAP (31).A 2.3 mm BICAP hemostatic probe with a sigmoidoscope and a 3.2 mm probe with a rigid anoscope were connected to a 50 W bipolar generator.Electrocoagulation was applied to bleeding sites at a power setting of 5 with pulse durations of 2 s.Treatment sessions were repeated two days later until hemostasis was achieved.All bleeding stopped after 3.8 sessions on average (range three to five).No complications were noted.No bleeding recurred after an average of 12 months of follow-up.The authors considered BICAP to be an easier, likely safer, much cheaper and equally effective therapy compared with laser.

CONCLUSIONS
In more than half of radiation proctitis cases, symptoms can be reasonably controlled with rectal steroid alone or in combination with oral sulfasalazine or sucralfate enemas.Laser treatment can be an effective therapy; however, specific requirements should be met.Formalin appears to be a simple, effective and inexpensive treatment, but more studies are required.Other therapies such as 5-ASA enemas, hydrocortisone acetate, HBO therapy and BICAP likewise require more studies.Controlled studies using a placebo only, however, would be difficult due to the usual severity of the patient's symptoms (bleeding), and thus controlled studies are best done comparing different modalities of therapy.