Non-surgical interventions for late rectal consequences of radiotherapy in people who have received radical radiotherapy to the pelvis

Background

Radiotherapy is often used to treat cancer in the pelvic area. Several organs in the pelvis, such as the anus, rectum, bladder, prostate, gynaecological organs (womb, ovaries, cervix, and vagina), small bowel, and pelvic bones may be exposed to the effects of radiotherapy, which can lead to pelvic radiation disease. Symptoms from pelvic radiation disease may occur around the time of treatment (early effects) or over a period of time, often many years after treatment (late effects) due to long-term changes secondary to scarring (fibrosis), narrowing (stenosis), and bleeding due to new blood vessel formation (telangiectasia). Damage to the rectum (radiation proctopathy) is the most often investigated late radiation effect to the pelvis, which affects a small but but still important group of people who undergo pelvic radiotherapy. The common symptoms are rectal urgency, rectal incontinence, pain, mucus discharge, and rectal bleeding.

The aim of the review

The aim of this review was to assess the effect of non-surgical treatments on late rectal damage.

Main Findings

We found 16 (quasi) randomised controlled trials (RCTs) including 993 participants that assessed non-surgical treatments for radiation proctopathy. Although some treatments look promising (including rectal sucralfate, adding metronidazole to an anti-inflammatory regimen, and hyperbaric oxygen therapy), the quality of evidence was low to very low. Furthermore, outcomes important to people with cancer, including quality of life (QoL), and long-term effects were often not addressed in these studies.

Conclusions

Although some interventions for late radiation rectal damage are promising, the evidence was of low quality and we can draw no firm conclusions. We could not combine data from the studies to compare different treatments, since the trial designs and outcome measures differed. The episodic and variable nature of late radiation rectal damage requires larger RCTs to establish whether treatments are effective. Future studies should address the possibility of associated injury to other pelvic structures, collectively known as pelvic radiation disease. Ideally outcome measures should be standardised across studies and include QoL evaluations and other outcomes important to people with cancer .

Quality of the evidence

The quality of the evidence for the majority of outcomes was low or very low, mainly due to the small size of most studies and study limitations.

Authors' conclusions: 

Although some interventions for late radiation proctopathy look promising (including rectal sucralfate, metronidazole added to an anti-inflammatory regimen, and hyperbaric oxygen therapy), single small studies provide limited evidence. Furthermore, outcomes important to people with cancer, including quality of life (QoL) and long-term effects, were not well recorded. The episodic and variable nature of late radiation proctopathy requires large multi-centre placebo-controlled trials (RCTs) to establish whether treatments are effective. Future studies should address the possibility of associated injury to other gastro-intestinal, urinary, or sexual organs, known as pelvic radiation disease. The interventions, as well as the outcome parameters, should be broader and include those important to people with cancer, such as QoL evaluations.

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Background: 

This is an update of a Cochrane review first published in 2002, and previously updated in 2007. Late radiation rectal problems (proctopathy) include bleeding, pain, faecal urgency, and incontinence and may develop after pelvic radiotherapy treatment for cancer.

Objectives: 

To assess the effectiveness and safety of non-surgical interventions for managing late radiation proctopathy.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2015); MEDLINE (Ovid); EMBASE (Ovid); CANCERCD; Science Citation Index; and CINAHL from inception to November 2015.

Selection criteria: 

We included randomised controlled trials (RCTs) comparing non-surgical interventions for the management of late radiation proctopathy in people with cancer who have undergone pelvic radiotherapy for cancer. Primary outcomes considered were: episodes of bowel activity, bleeding, pain, tenesmus, urgency, and sphincter dysfunction.

Data collection and analysis: 

Study selection, 'Risk of bias' assessment, and data extraction were performed in duplicate, and any disagreements were resolved by involving a third review author.

Main results: 

We identified 1221 unique references and 16 studies including 993 participants that met our inclusion criteria. One study found through the last update was moved to the 'Studies awaiting classification' section. We did not pool outcomes for a meta-analysis due to variation in study characteristics and endpoints across included studies.

Since radiation proctopathy is a condition with various symptoms or combinations of symptoms, the studies were heterogeneous in their intended effect. Some studies investigated treatments targeted at bleeding only (group 1), some investigated treatments targeted at a combination of anorectal symptoms, but not a single treatment (group 2). The third group focused on the treatment of the collection of symptoms referred to as pelvic radiation disease. In order to enable some comparison of this heterogeneous collection of studies, we describe the effects in these three groups separately.

Nine studies assessed treatments for rectal bleeding and were unclear or at high risk of bias. The only treatments that made a significant difference on primary outcomes were argon plasma coagulation (APC) followed by oral sucralfate versus APC with placebo (endoscopic score 6 to 9 in favour of APC with placebo, risk ratio (RR) 2.26, 95% confidence interval (CI) 1.12 to 4.55; 1 study, 122 participants, low- to moderate-quality evidence); formalin dab treatment (4%) versus sucralfate steroid retention enema (symptom score after treatment graded by the Radiation Proctopathy System Assessments Scale (RPSAS) and sigmoidoscopic score in favour of formalin (P = 0.001, effect not quantified, 1 study, 102 participants, very low- to low-quality evidence), and colonic irrigation plus ciprofloxacin and metronidazole versus formalin application (4%) (bleeding (P = 0.007, effect not quantified), urgency (P = 0.0004, effect not quantified), and diarrhoea (P = 0.007, effect not quantified) in favour of colonic irrigation (1 study, 50 participants, low-quality evidence).

Three studies, of unclear and high risk of bias, assessed treatments targeted at something very localised but not a single pathology. We identified no significant differences on our primary outcomes. We graded all studies as very low-quality evidence due to unclear risk of bias and very serious imprecision.

Four studies, of unclear and high risk of bias, assessed treatments targeted at more than one symptom yet confined to the anorectal region. Studies that demonstrated an effect on symptoms included: gastroenterologist-led algorithm-based treatment versus usual care (detailed self help booklet) (significant difference in favour of gastroenterologist-led algorithm-based treatment on change in Inflammatory Bowel Disease Questionnaire–Bowel (IBDQ-B) score at six months, mean difference (MD) 5.47, 95% CI 1.14 to 9.81) and nurse-led algorithm-based treatment versus usual care (significant difference in favour of the nurse-led algorithm-based treatment on change in IBDQ-B score at six months, MD 4.12, 95% CI 0.04 to 8.19) (1 study, 218 participants, low-quality evidence); hyperbaric oxygen therapy (at 2.0 atmospheres absolute) versus placebo (improvement of Subjective, Objective, Management, Analytic - Late Effects of Normal Tissue (SOMA-LENT) score in favour of hyperbaric oxygen therapy (HBOT), P = 0.0019) (1 study, 150 participants, moderate-quality evidence, retinol palmitate versus placebo (improvement in RPSAS in favour of retinol palmitate, P = 0.01) (1 study, 19 participants, low-quality evidence) and integrated Chinese traditional plus Western medicine versus Western medicine (grade 0 to 1 radio-proctopathy after treatment in favour of integrated Chinese traditional medicine, RR 2.55, 95% CI 1.30 to 5.02) (1 study, 58 participants, low-quality evidence).

The level of evidence for the majority of outcomes was downgraded using GRADE to low or very low, mainly due to imprecision and study limitations. 

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