Radiation Proctitis

Etiology

Radiation proctitis occurs as a result of radiation therapy for malignancy to organs in the pelvis, including the prostate, rectum, and reproductive organs. The degree of radiation proctitis varies, depending on the modality by which the radiation is delivered, the radiation dose, and the volume of irradiated tissue. Several specific risk factors have been identified, such as a dose of radiation to the rectum >45 Gy, a history of inflammatory bowel disease, HIV/AIDS, and a possible genetic predisposition.[2][3][4][5]

Epidemiology

It is difficult to assess the true incidence of radiation proctitis. There are several large series that estimate chronic radiation proctitis to be anywhere between 5% to 11% of patients treated with radiation therapy.[6] Almost 90% of patients who go on to experience chronic radiation proctitis will present in the first 2 years after treatment.[7][8]

The frequency of radiation proctitis exhibits variations across sexes and age groups, both in the United States and globally. While the prevalence rates can be influenced by the specific demographics of cancer incidence and treatment practices, some general patterns emerge. In the U.S., the occurrence of radiation proctitis is observed in both males and females undergoing pelvic radiation therapy for malignancies such as prostate, cervical, and rectal cancers. The incidence may differ based on the distribution of these cancers within each gender. Additionally, age plays a role, with older individuals more commonly affected due to the higher prevalence of cancer in this demographic.

Globally, the frequency of radiation proctitis is influenced by regional variations in cancer prevalence, treatment protocols, and healthcare infrastructure. In areas where pelvic malignancies are more prevalent or where radiation therapy is a common treatment modality, the incidence of radiation proctitis may be higher.

Pathophysiology

Radiation therapy works by damaging cells through the direct effect of ionizing radiation on DNA, lipids, and proteins.[9] Water makes up the majority of the cell, and ionizing radiation results in the creation of oxygen-free radicles. The direct effect of ionizing radiation also disrupts vital cellular proteins and DNA, causing cellular necrosis. Early radiation injury causes edema, mucosal hyperemia, and ulceration of the affected tissue.

The epithelium of the bowel is rapidly proliferating, and as such, it is more predisposed to the effects of radiation damage. Chronically, there is intimal proliferation and hyaline thickening of the media of arterioles.[10] Hypertrophy of rectal smooth muscle occurs, which can affect compliance and defecation as the rectum's ability to distend is diminished.[11] This is further worsened by fibrosis of the serosa.

History and Physical

Patients experiencing radiation proctitis may present with malabsorption, perforation, bowel obstruction, bleeding, and stricture formation. They can also present with fistulous disease. If the anal sphincter is directly involved in the radiation field, patients may present with fecal incontinence.

It is essential to consider a recurrent malignancy in patients who present several years after their radiation therapy with symptoms of malabsorption, abdominal pain, increased frequency of bowel movements, bleeding, etc. While these symptoms may be due to radiation proctitis, they may also signify a local recurrence.

In terms of physical examination, a focused abdominal examination and, most importantly, a digital rectal exam should be performed to identify any anorectal stenosis. The examination can be painful for patients and may not be able to be completed in the office setting, in which case an examination under anesthesia is indicated.

Evaluation

After completing a thorough history and physical examination, the next step is to perform either a rigid or flexible sigmoidoscopy. An experienced colorectal surgeon or gastroenterologist should perform this exam with minimal insufflation as the inflamed bowel is more susceptible to perforation, especially as it becomes fixated. The examination is likely to reveal a friable mucosa with a multitude of changes, including edema, oozing, and ulcerations.[12][13]

The mucosa may sometimes appear similar to that seen in inflammatory bowel disease with pseudopolyp formation. Areas of ulceration may require a biopsy, but this must be done cautiously (see Image. Colonoscopy of Radiation Proctitis, Moderate-to-Severe). There are likely to be multiple areas of strictures that can be indistinguishable from recurrent malignancy.[14]

Barium or water-soluble enema studies may also be performed, which can identify strictures, obstruction, shortening, and narrowing of the rectosigmoid area with loss of the normal curvature. It may also demonstrate decreased compliance of the rectum. The presacral space may appear to be increased due to rectal wall thickening.[15]

Once the diagnosis of radiation proctitis has been established, several grading systems exist to gauge severity, including RTOG/EORTC and LENT-SOMA. 

Treatment / Management

Primary Prevention

Prophylactic medical therapies such as sucralfate, amifostine, and misoprostol have failed to demonstrate a reduction in the risk of proctitis in patients undergoing pelvic radiotherapy. However, data suggests that selenium supplementation taken during radiation treatments may reduce the risk of grade 2+ diarrhea. A small randomized trial of patients undergoing pelvic radiotherapy for uterine and cervical cancer taking 500 mg of selenium versus placebo demonstrated a significant reduction in the rate of grade 2+ diarrhea (20.5% vs 44.5%).[16]  (A1)

Another avenue to minimize the risk of proctitis is the radiation planning and delivery process. Most of the data regarding late rectal complications are derived from the treatment of prostate cancer. There is a consistent dose-volume relationship with the risk of grade ≥2 rectal toxicity across several studies, specifically the volume of rectum receiving ≥60 Gy.[2] This emphasizes the importance of radiation delivery and the planning process in preventing late rectal toxicities. Several dose constraints have been put forward. For conventionally fractioned radiotherapy, the V50 <50%, V65 <25%, V70 <20%, and V75 <15% have been used, although they were derived from the 3D treatment era and easily met Intensity Modulated Radiotherapy (IMRT).[2] The QUANTEC dose constraints are a conservative starting point that, if adhered to, predict a grade ≥2 late rectal toxicity <15%.[2] Rectal constraints also exist for hypofractionated radiotherapy and stereotactic body radiotherapy (SBRT). (A1)

While adherence to established dose constraints is essential, how radiotherapy is delivered can also influence the risk of late rectal toxicity. When comparing 3D conformal treatment to IMRT when treating the pelvis, the incidence of late rectal toxicity appears to be lower with IMRT in the treatment of genitourinary and gynecologic malignancies. Late rectal toxicity in patients treated with 3D radiation for prostate cancer was 13% versus 5% in those treated with IMRT.[17] Postoperative endometrial and cervical cancer patients treated with IMRT also demonstrate lower rates of late gastrointestinal (GI) toxicity compared to 3D conformal (42% vs 21%).[18][19] Despite the claims that proton therapy will lead to even lower rates of toxicity, the data suggest that proton therapy, at best, has no effect and, at worst, may have higher rates of GI toxicity compared to IMRT for patients with prostate cancer.[20][21]  (A1)

Improvements in daily image guidance also contribute to the reduction of late rectal toxicity as they allow for tumor and normal tissue motion to be taken into account, allowing for smaller planning target volumes (PTV) margins. Retrospective analysis of prostate cancer patients treated with IMRT and image guidance demonstrated a reduction in 3-year late rectal toxicity compared to those treated with IMRT without image guidance (4.1% vs 13.1%).[22] 

Other preventative methods include introducing a physical space between the rectum and the target structure. Hyaluronic acid spacers involve the injection of a gel into the perirectal fat, thus enlarging the space between the anterior rectal wall and the posterior aspect of the prostate. Randomized multicenter data have demonstrated not only improved rectal V50-80 dosimetric parameters but also a reduction in late rectal toxicity with no patients experiencing >1 grade toxicity. There were no differences in acute rectal toxicity.[23](A1)

Medical Interventions

Acute Proctitis

If primary prevention fails, patients may develop acute radiation proctitis during treatment or within 6 months posttreatment. Acute proctitis is self-limited for most patients, and treatment is largely supportive. Unfortunately, many of these interventions lack evidence to support their use but are nevertheless utilized to address symptoms such as diarrhea, tenesmus, and rectal urgency. Patients who develop acute GI toxicity during treatment have a 42% ten-year likelihood of late GI toxicity compared to 9% in those who did not experience acute side effects.[17] Antimotility agents such as loperamide and diphenoxylate are used for patients experiencing diarrhea. Other symptoms, such as rectal urgency and tenesmus, have been treated with sodium butyrate, a short-chain fatty acid. A small randomized crossover trial of patients undergoing pelvic radiotherapy demonstrated a clear remission of symptoms with topical sodium butyrate compared to saline enemas.[24] Other therapies include mesalamine or corticosteroid enemas. In cases of extreme discomfort, treatment may be suspended to allow some tissue recovery and symptom resolution, but this delay may adversely affect the oncological outcome.(A1)

Chronic Proctitis

Patients who develop chronic proctitis over the ensuing months to years after treatment have several medical treatment options. Evidence for the various treatments ranges from anecdotal to small randomized prospective trials.

Some studies found sucralfate enemas helpful, with clinical improvement in 73% of patients who received pelvic radiotherapy and had continued tenesmus and rectal bleeding.[25] A prospective randomized, double-blind study comparing sucralfate enemas to rectal sulfasalazine and prednisone demonstrated better tolerance of sucralfate and superior clinical response. Ninety-two percent of patients had a significant reduction in rectal bleeding at the 4-month follow-up.[26] A possible mechanism of action is the repair of microvascular damage through the stimulation of angiogenesis and glutathione production.[27](A1)

Formalin (ie, formaldehyde 4% to 10%) has been studied and used to treat chronic radiation proctitis for over 20 years.[28] The advantages of formalin treatment are that it can be utilized in the clinical setting without general anesthesia and with only light sedation. The mechanism of action of formalin is the chemical cauterization of the ulcers and telangiectasias, which are the source of bleeding in chronic proctitis. The formalin can be applied with the direct application of a gauze that has been soaked in formalin and the direct application of it to the mucosa of the affected areas, usually under direct vision using rigid proctoscopy. The concentration of formalin is typically 4%, although some studies have utilized a 10% solution. A study from Poland showed that after the first application, 50% of the patients had complete resolution of their symptoms, and most patients required an average of 2 treatments.[29] (B3)

Glucocorticoid suppositories have also been utilized for patients with continued rectal bleeding. The anti-inflammatory effects are thought to lead to symptomatic improvement. However, an open randomized trial of mesalamine suppositories versus hydrocortisone foam demonstrated higher rates of hematochezia and mucus in the stool after 2 weeks of treatment with hydrocortisone foam.[30](A1)

The latest clinical consensus guidelines from the American Society of Colon and Rectal Surgery suggest that short-chain fatty acid enemas are not useful in treating chronic radiation proctitis.[31] Over the years, there have been investigations into other treatments, including ozone therapy, mesalamine, and metronidazole. However, no evidence exists to support their efficacy.[32] (A1)

In patients who are refractory to medical treatment, hyperbaric oxygen therapy (HBO) has reasonable evidence to support its use for radiation proctitis.[33][34] A randomized trial of 2.0 atm vs 1.1 atm demonstrated a significant improvement in healing responses and late effects normal tissue-subjective, objective, management, and analytic (LENT-SOMA) scores.[35] A Cochrane review of HBO therapy concluded it is a safe and likely efficacious intervention for patients with refractory radiation proctitis.[36](A1)

Several studies have demonstrated that endoscopic argon beam plasma coagulation can reduce bleeding by approximately 79% to 100%.[37] This treatment is not without adverse effects. Complications include rectal ulcerations and fistula formation. While endoscopic argon beam plasma coagulation treatment has been substantiated, other endoscopic treatments, such as bipolar electrocoagulation, radio-frequency ablation, and Nd-YAG laser, have not been sufficiently studied.[32](A1)

Patients may develop strictures and present with obstructive symptoms that may not respond to stool softeners. Endoscopic Savary-Gilliard dilatation may be used in patients with short strictures that are not responsive to medical therapy. In patients with longer strictures, surgery may be preferable.

Surgery is reserved for patients who do not show improvement in their symptoms following the above medical and endoscopic interventions. It is also used for some of the more severe complications that are associated with radiation proctitis, including strictures that may lead to large bowel obstruction, fistulas, or even perforation. Studies have estimated that only 10% of patients with radiation proctitis will ultimately require operative intervention.[38] In very severe cases, a proctectomy may be necessary. However, studies have demonstrated that diversion in the form of an ileostomy or colostomy may improve quality of life, and no further surgical procedures may be needed.[39](B2)

Differential Diagnosis

The differential diagnosis of radiation proctitis involves careful consideration of various conditions that may present with similar symptoms or findings. Clinicians must distinguish radiation proctitis from other causes of rectal inflammation, bleeding, and GI distress.

Radiation proctitis must be distinguished from other etiologies of infectious and noninfectious dysentery, including:

• Diverticulitis
• Crohn disease
• Irritable bowel disease
• Infectious colitis
• Recurrence of malignancy

Given the potential overlap in clinical presentations, a meticulous evaluation, including endoscopic procedures, histological examination, and imaging studies, is essential to ensure an accurate and timely diagnosis of radiation proctitis and appropriate differentiation from other potential etiologies.

Prognosis

The prognosis depends on the severity of the individual patient's disease. Up to 30% of patients with severe symptoms may have a significant decrease in health-related quality of life.[40] Patients with radiation proctitis are also at risk of developing a secondary malignancy, of which the majority are colon or rectal cancers.[41]

In many cases, acute radiation proctitis tends to be self-limiting, with symptoms resolving once radiation therapy concludes. However, the prognosis becomes more nuanced when the condition progresses to its chronic phase, occurring more than 3 months posttreatment. Chronic radiation proctitis can lead to persistent symptoms, impacting the patient's quality of life. While some individuals may experience manageable symptoms with conservative management, others may face more challenging complications, such as rectal strictures or fistulas, influencing long-term outcomes. Early detection, proactive monitoring, and a tailored treatment approach can significantly improve the prognosis by addressing symptoms promptly and mitigating the risk of severe complications. 

Complications

The complications of radiation proctitis can significantly impact the quality of life of individuals undergoing pelvic radiation therapy and include the following:

• Colitis
• Bowel perforation
• Sepsis
• Fistula formation
• Radiation associated malignancies

In its acute phase, patients may experience symptoms such as diarrhea, rectal bleeding, and abdominal pain. However, the transition to chronic radiation proctitis, occurring more than 3 months posttreatment, can lead to persistent and potentially severe complications. Chronic symptoms may include rectal strictures, fecal urgency, and incontinence, posing substantial challenges to daily activities. In some cases, radiation proctitis can progress to more severe outcomes, such as fistulas or perforations, necessitating surgical intervention. The complexity of managing these complications underscores the importance of proactive monitoring, early intervention, and a multidisciplinary approach to provide comprehensive care for individuals affected by radiation proctitis.