Diagnosis and treatment of chronic radiation proctitis

see the discussion about using hyperbaric oxygen for radiation proctitis here


INTRODUCTION Radiation injury to the lower intestine may be encountered following treatment of cancers of the rectum, cervix, uterus, prostate, urinary bladder, and testes. Thus, the rectum and sigmoid colon are most often affected.

DEFINITIONS The type of injury caused by radiation exposure can be divided into two categories: acute and chronic.

  • Acute radiation injury occurs during and within six weeks of therapy. Symptoms include diarrhea and rectal urgency or tenesmus, and, uncommonly, bleeding. These symptoms usually resolve without specific therapy within two to six months, although some patients report persistent symptoms for at least one year [3]. Topical butyrate enemas may accelerate healing
  • Chronic radiation proctitis has a more delayed onset. The first signs often occur at about 9 to 14 months following radiation exposure, but may develop after more than two years in some patients and rarely up to 30 years after exposure

Late radiation injury is due to progressive epithelial atrophy and fibrosis associated with obliterative endarteritis and chronic mucosal ischemia. The end result is a chronically ischemic intestinal segment that is prone to stricture formation and bleeding. The term "proctitis" is somewhat misleading since it inaccurately implies a chronic inflammatory condition. As a result, authorities prefer to refer to it as a chronic radiation "proctopathy". However, because radiation proctitis is still used commonly, it will be used in this topic review.

Symptoms include diarrhea, obstructed defecation (in patients who have developed strictures), bleeding, rectal pain or urgency, and less commonly fecal incontinence. Subtler symptoms and concomitant injury to the genitourinary tract or small bowel may be associated with a significant decrease in health-related quality of life in up to 30 percent of patients. These complications include fistulas, small bowel obstruction, small bowel bacterial overgrowth, urethral stenosis, and cystitis. Radiation exposure also increases the risk of secondary malignancy including colorectal cancer, which usually occurs more than 10 years after exposure

The diagnosis, and treatment of chronic radiation proctitis will be reviewed here. The incidence of radiation proctitis and the modalities that can be used to prevent this complication are discussed separately.

DIAGNOSIS Chronic radiation proctitis or sigmoiditis should be suspected in patients who have the above clinical features developing nine months or more after pelvic radiation exposure. In most patients, the diagnosis can be confirmed during colonoscopy or sigmoidoscopy. Mucosal features consistent with radiation injury include pallor with friability, and telangiectasias, which can be multiple, large, and serpiginous; these changes tend to be continuous.

Although mucosal biopsies are not diagnostic, they can help to exclude other causes of proctitis such as infection or inflammatory bowel disease

There is a concern related to fistula formation from obtaining rectal biopsies over the prostate. It is likely that patients in whom this occurred had severe necrosis and hence the contribution of the biopsy to the fistula formation is unclear. Rectal biopsies should be performed judiciously depending upon the clinical indication as well as the dose and fractionation of previous pelvic radiation therapy. If required, they should be directed at the posterior and lateral walls to avoid the irradiated areas.

Barium studies are helpful in patients who have obstructive symptoms and are preferred in those suspected of having fistulas. In such patients, a CT scan may also be necessary to exclude recurrent malignancy.

TREATMENT There have been no large controlled trials evaluating treatment of radiation proctitis or proctosigmoiditis. Thus, experience is derived mostly from case reports and small clinical trials. A systematic review focusing on six trials that included a control group  found that there were insufficient data to make firm conclusions regarding any therapy although some treatments (including rectal sucralfate, metronidazole combined with topical anti-inflammatory treatment, and heater probe application) appeared promising

Treatment should be based upon the pattern and severity of symptoms. No specific therapy is required in patients whose symptoms are mild, such as those with small amounts of rectal bleeding in whom symptoms may improve spontaneously. In one series, for example, bleeding subsided spontaneously within six months in 35 percent of patients who initially had only mild rectal bleeding. In contrast, patients whose symptoms are more severe may not have such a favorable prognosis. Several approaches have been tried in these patients.

Stool softeners Stool softeners may be helpful in patients who have mild obstructive symptoms related to strictures.

Dilation Balloon or Savary-Guillard dilation can be effective in patients with obstructive symptoms from strictures who do not respond to stool softeners provided that the strictured segment is short. The risk of perforation is increased in patients with long or angulated strictures. Such patients may require surgery if obstruction is significant clinically.

Sulfasalazine and aminosalicylates The efficacy of sulfasalazine and aminosalicylates in idiopathic ulcerative colitis prompted their use in radiation proctitis given as oral or enema preparations. Although some reports and anecdotal experience have suggested that this approach may be successful, other series have been disappointing.

The addition of rectal prednisolone enemas to oral sulfasalazine improved symptoms in a controlled trial in which combined therapy was compared to sucralfate enemas. The efficacy of corticosteroid enemas alone has been poorly studied. However, clinical experience with this approach has been disappointing.

Sucralfate Several reports have suggested that topical sucralfate may improve symptoms in radiation proctitis or proctosigmoiditis. The rationale for its use is based upon its favorable effects on epithelial associated microvascular injury

In a prospective, double-blind trial, 37 patients with proctosigmoiditis were randomly assigned to a four-week course of oral sulfasalazine (3.0 g/day) plus prednisolone enemas (20 mg BID) or sucralfate enemas (2.0 g BID). Clinical improvement was noted in both groups at the end of the study. However, the response was better for sucralfate enemas, which were also better tolerated.

Another report from the same authors included 26 patients with moderate to severe radiation proctosigmoiditis who were treated with sucralfate enemas (20 mL of a 10 percent suspension twice daily) until bleeding stopped or failure of therapy was acknowledged. The response was considered good when the severity of bleeding improved by at least two grades, which was defined by the number of episodes of bleeding per week. A good response was observed in 77 percent of patients by four weeks, and 92 percent by 16 weeks. These results await confirmation in larger controlled trials.

Sucralfate has also been evaluated for prophylaxis against acute radiation injury. However, placebo-controlled phase III trials have detected no benefit from either topical or oral sucralfate

Hormonal therapy Hormonal therapy with estrogen (with or without progesterone) has been used to control obscure gastrointestinal bleeding in patients with Osler-Weber-Rendu syndrome, von Willebrand's disease, end-stage renal disease, and angiodysplasia alone. Although experience with treating radiation proctosigmoiditis is limited, at least one case series suggested a possible benefit. However, side effects of hormonal therapy observed during treatment of patients with angiodysplasias are common, and the efficacy of therapy has not been uniform.

Hyperbaric oxygen The theoretical benefit of hyperbaric oxygen therapy (HBO) may be via inhibition of bacterial growth, preservation of marginally perfused tissue, and inhibition of toxin production. HBO has been used for treatment of refractory foot ulcers in diabetes and in other conditions.

Observational series have suggested that HBO may have a role in the treatment of chronic radiation proctitis. One of the largest series included 27 men who had been irradiated for prostate cancer. HBO resulted in a resolution of fecal urgency and a complete resolution of bleeding in approximately half of the patients and improved rectal pain in 75 percent, but no patient had complete relief of pain. Ulcers can worsen under therapy.

The equipment needed for hyperbaric oxygen treatment is expensive and not widely available. Thus, at the present time, it is not a practical means of treating chronic radiation proctitis outside of centers specializing in this approach, particularly since its effectiveness has not been well-studied.

Short-chain fatty acid enemas Short-chain fatty acids (SCFAs) are the preferred luminal nutrients for colonocytes. SCFA enemas have been effective for treatment of diversion colitis, prompting their study in radiation proctitis. Although case reports suggested a possible benefit, no significant improvement in symptoms was found in a placebo controlled study

Pentosan polysulfate Pentosan polysulfate is a low-molecular weight heparin-like compound with anticoagulant and fibrinolytic effects, which has been approved for the treatment of interstitial cystitis. Although a phase I/II pilot studied suggested benefit, a phase III trial that randomly assigned 180 patients to placebo or one of two doses of pentosan found no improvement in radiation-induced symptoms

Metronidazole The efficacy of metronidazole was evaluated in study that included 60 patients with rectal bleeding and diarrhea who were randomly assigned to treatment with mesalazine plus betamethasone enemas with or without metronidazole (400 mg orally three times daily). The incidence of rectal bleeding and mucosal ulcers was lower in the metronidazole groups at four weeks, three months, and 12 months. Diarrhea and edema were also reduced in the metronidazole group.

Formaldehyde Formaldehyde induces coagulative tissue necrosis on contact, providing a rationale for its use in patients with radiation proctitis who have significant bleeding. Several series (using variations in technique) have described improvement or cessation of bleeding. The procedure has generally been well tolerated, although serious complications including the development of fistulas requiring colostomy and bowel necrosis requiring resection have also been described. Direct contact of the formalin with the anoderm can be extremely irritating to the skin and should be avoided. The following illustrate the range of findings.

  • In one report, 29 patients with severe bleeding from radiation proctitis that had been refractory to other types of therapy were treated by the application of 4 percent formalin-soaked gauze to the affected areas in the rectum via a rigid sigmoidoscope for as long as was required to achieve hemostasis. One month after therapy, 17 patients had complete cessation of bleeding and 11 only had minor bleeding. After a median of 12 months, bleeding had stopped completely in 22 of the 29 patients (76 percent). Treatment was generally well-tolerated. One patient had worsening of a radiation-induced stricture that required dilation.
  • A later series included 33 patients, 23 of whom required one formalin application while 10 required a second application because of persistent bleeding. Treatment was considered to be effective in 23 patients (70 percent); 13 had complete cessation of bleeding while 10 had only minor bleeding. Six anal or rectal strictures developed after treatment and fecal incontinence worsened in five patients and developed in an additional four patients. The authors concluded that formalin application was effective but morbidity was not negligible. Many of the patients who developed complications had been treated for anal cancer (four of the six patients who developed a stricture and in all five of the patients who developed worsening incontinence) possibly explaining the increased morbidity compared with other series.
  • In a variation on the technique, 20 mL of a 5 percent formalin solution were instilled into the rectum during flexible sigmoidoscopy without sedation. A single session was effective in controlling bleeding in 13 of 20 patients (65 percent) while four responded to a second treatment. Average follow-up was 23 months. There were no serious complications but the sample size was small.
  • Another series described 100 patients who were treated by direct application of a 10 percent buffered formalin solution to the affected area using a 16-inch cotton tip applicator. Treatment was applied through a proctoscope in the office. Overall, 93 percent of patients had cessation of bleeding after an average of 3.5 applications at two to four week intervals. Three patients complained of anal pain and one dizziness after the procedure.

Antioxidants The possible role of oxidative injury in chronic radiation proctitis provided the rationale for a study of antioxidants. A small uncontrolled study involving 10 patients suggested that treatment with vitamin E (400 IU three times daily) and vitamin C (500 mg three times daily) was associated with improvement in diarrhea and urgency The high dropout rate in the study (only one-half of the originally treated patients were available for follow-up), the relatively subjective endpoints used, and the absence of a control group make it difficult to draw any conclusions. Controlled trials are awaited.

Vitamin A A potential role for oral retinol palmitate was suggested in a pilot, placebo controlled trial involving 18 patients with radiation proctitis. Response (defined as a reduction in two or more symptoms by at least two points on a validated scale) was observed significantly more often in the group randomized to retinol palmitate. In addition, five placebo nonresponders subsequently responded to active treatment during crossover. The authors hypothesized that the benefit might be due to improved wound healing. Further studies are needed.

Endoscopic therapy A variety of endoscopic methods have been used to treat radiation colitis. Although most are best suited to treat bleeding, they may have additional benefits for other symptoms.

Changes in prostate radiation protocols in recent years, including combination implant and external beam irradiation with high radiation exposure, have been associated with rectourethral fistulas in the first six months to two years likely secondary to radiation-induced prostate necrosis and early and aggressive endoscopic treatment. Thus, all forms of treatment and biopsies should be coordinated with the radiation urologist.

Argon plasma coagulation Argon plasma coagulation (APC) uses high frequency energy transmitted to tissue by ionized gas. It has been used to treat a wide spectrum of bleeding lesions in the gastrointestinal tract.

The efficacy of APC has been suggested in several case series. One of the largest reports, for example, included 28 patients with persistent bleeding despite medical therapy. The majority of patients had improvement in bleeding and anemia after a median of 2.9 sessions (range one to eight). All visible lesions were targeted at each session and follow-up procedures were scheduled in four-week intervals to allow the tissue to heal The mean hemoglobin rose by 1.2 gm/dL and by 1.9 gm/dL among individuals presenting with anemia. Some patients experienced post-procedure rectal pain and cramps, but no major complications occurred. Other reports have demonstrated that APC may control bleeding even after unsuccessful treatment using other methods. Special care is required to avoid spraying too close to the dentate line.

5-ASA suppositories and/or cortifoam enemas are often used to help treat rectal ulceration associated with APC. Treatment-related ulcers (present in more than one-half of patients) should be avoided during subsequent sessions . A complete bowel lavage is probably safest before each procedure. A potential complication if this is not done is bowel explosion with perforation, presumably due to the accumulation of combustible colonic gas

Lasers The argon and Nd:YAG laser have been used to coagulate bleeding ectatic vessels throughout the gastrointestinal tract. These devices are not widely available.

The potential benefit of this approach was illustrated in a report in which the Nd:YAG laser was used in nine patients, of whom six required periodic transfusion: bleeding was reduced to only occasional spotting in six patients, with only one continuing to require periodic transfusions during follow-up of 24 months.

Bipolar and heater probe Bipolar electrocoagulation (BiCap) and the heater probe have several advantages compared to laser therapy. They cause less tissue injury, permit tangential application of cautery, and the equipment needed is widely available and relatively inexpensive.

These techniques were evaluated in a study involving 21 patients with chronic recurrent hematochezia and anemia due to radiation-induced injury who were followed for 12 months. Patients were treated with either BiCap or heater probe therapy as needed. Severe bleeding diminished significantly after these treatments compared to the previous twelve months of medical therapy (75 versus 33 percent and 67 versus 11 percent, respectively). The decreased rate of bleeding was accompanied by an improvement in hematocrit in both groups. There were no major complications.

Surgery Surgery should be reserved for patients who have intractable symptoms such as strictures, pain, or bleeding, since it may be technically demanding due to adhesions and other radiation damage in the pelvis. Another problem is that anastomoses involving radiated tissue can break down. Thus, extensive disease is unlikely to have a good outcome.

However, good results can be achieved in experienced hands. In addition, total rectal resection may be the only option in some patients. In this setting, construction of an ileocecal reservoir has been associated with a good functional outcome.

PREVENTION The specific techniques used to deliver radiation therapy as well as dose fractionation influence the likelihood of developing radiation injury. In addition, medical prophylaxis with amifostine may help prevent injury These issues are discussed separately.

SUMMARY AND RECOMMENDATIONS

  • Chronic radiation proctitis should be suspected in patients who have compatible clinical features developing nine months or more after pelvic radiation exposure. Symptoms include diarrhea, obstructed defecation (in patients who have developed strictures), bleeding, rectal pain or urgency, and less commonly fecal incontinence.

Mucosal features consistent with radiation injury include pallor with friability, and telangiectasias, which can be multiple, large, and serpiginous; these changes tend to be continuous. Although mucosal biopsies are not diagnostic, they can help to exclude other causes of proctitis such as infection or inflammatory bowel disease. Because of a concern related to fistula formation, rectal biopsies should be performed judiciously depending upon the clinical indication as well as the dose and fractionation of previous pelvic radiation therapy. If required, they should be directed at the posterior and lateral walls to avoid the irradiated areas.

  • The selection among the treatment options discussed above should be based upon the type of symptoms and their severity, and experience within the treatment center. As mentioned above, specific therapy may not be necessary in those who have only mild symptoms, such as occasional hematochezia or mild tenesmus.

Obstructive symptoms

  • We suggest stool softeners in patients who have mild obstructive symptoms related to strictures. In those with narrower strictures, we suggest balloon or Savary-Guillard dilation provided that the strictured segment is short . The risk of perforation is increased in patients with long or angulated strictures. Such patients may require surgery.

Bleeding

As noted above, mild bleeding may not require treatment since bleeding may remit spontaneously within six months in up to one-third of more of these patients. Several options are available in patients with persistent or more severe bleeding.

  • Because medical therapy is safe and may be effective, we suggest a trial of sucralfate (Carafate) enema therapy. Although experience is limited, sucralfate enemas (20 mL of a 10 percent sucralfate suspension in water twice daily) were more effective than oral sulfasalazine even when combined with corticosteroid enemas.
  • For nonresponders, we suggest a trial of the endoscopic methods discussed above. Most clinicians dealing with radiation proctitis prefer APC because of ease of use and predictable response. Formalin application may be an acceptable alternative, which may also reduce the need for recurrent procedures that are often required with the endoscopic methods. However, the possibility of serious complications requiring bowel resection or colostomy should be considered when weighing alternatives.

The timing of these approaches should be coordinated with a radiation oncologist/urologist. As noted above, aggressive endoscopic therapy in the setting of prostate necrosis may be associated with an increased risk of fistula formation.

Tenesmus and rectal pain

  • In patients with tenesmus or rectal pain we suggest sucralfate or corticosteroid enemas. In comparison, 5-ASA enemas do not appear to be helpful in this setting. While oral 5-ASA or sulfasalazine continue to be used in clinical practice, evidence supporting their benefit in this setting is limited.