Pharmacological interventions for the prevention and treatment of radiation colitis, enteritis and proctitis

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The aim of the study is to assess the efficacy of different pharmacological therapies for the treatment and prevention of radiation colitis, enteritis and proctitis in patients who are past recipients of radiation therapy.

Background

Two years after the advent of radiation therapy in 1895, Walsh 1897 described the first case of "deep tissue damage to the intestinal tract" following ionizing radiation. Walsh 1897 believed that radiation caused direct inflammation of the intestinal mucosa. Warren 1922reported similar findings in the first systematic study of radiation induced injury.

Over the years as the number of cancer survivors who received radiotherapy has increased, the number of patients presenting with gastrointestinal complications has also climbed. The reported incidence of such complications has been as high as 50% and includes radiation enteritis, colitis and proctitis (Claben 1998; Gilinsky 1983; Ooi 1999; Gami 2003; Lundby 1997; Dahlberg 1998; Olopade 2004; Kozelsky 2003). These conditions greatly affect patients’ quality of life. Patients may present shortly after radiation therapy (acute) or it may be several years before these patients develop symptoms related to radiation injury (chronic).

Acute radiation injury may be self limited (Cho 2006), whereas the prognosis of chronic radiation injury remains obscure. Chronic radiation injury is associated with significant morbidity and mortality. Both its behavior and natural history are poorly understood and no consensus exists regarding clinical and endoscopic evaluation. There also remains an uncertainty on how to manage chronic radiation injury as well as the multiple long term adverse effects (for example, fistula formation, anastomotic strictures, perforation, abscesses and even cancer). These complications not only affect the patient's quality of life, but also place a substantial economic burden on the healthcare system with up to 17% of the patients requiring surgical intervention (Potosky 2000; Kollmorgen 1994; Mann 1991).

Description of the condition

The term radiation enteritis describes the inflammatory and degenerative changes seen within the small intestine after external‐beam radiation therapy to the abdominopelvic organs, at a dose of 8 Gy or higher. Colitis and proctitis are inflammation of the colon and the rectum respectively. All three entities i.e. enteritis, colitis and proctitis can be divided into acute and chronic groups based on the time of presentation.

Patients with acute inflammation or acute radiation injury (ARI) present during or shortly after radiotherapy. The injury to the intestines is caused by a direct effect of radiation on the bowel mucosa, damaging the DNA of cells. On histology, an inflammatory cell infiltrate is seen with reduced crypt mitoses (leading to mucosal atrophy) and crypt micro‐abscesses. Other findings include epithelial denudation and ulcerations. These changes are usually confined to the superficial mucosa and are reversible once the anti‐mitotic activity of ionizing radiation has been removed and the intestinal crypt cells are allowed to regenerate (Carr 1994; Berthrong 1981; Sher 1990; Hasleton 1985).

The presenting symptoms of acute radiation injury are multiple and are dependent on the site of involvement. Up to 80% of the patients receiving radiotherapy may develop symptoms during treatment. With acute enteritis, patients usually present with weight loss, nausea, vomiting and diarrhea, whereas patients with acute proctitis and colitis frequently have rectal bleeding, tenesmus (difficulty in evacuating stools), urgency, diarrhea and abdominal pain. In most cases these symptoms are self limited, lasting for a median of three months and require only supportive treatment (Cho 2006; Yeoh 1987; Carr 1994; Nussbaum 1993).

Chronic radiation injury (CRI) presents several months to years after radiotherapy and although a few cases have been reported 30 years post‐radiation treatment, the majority present after 8 to 48 months (Deveny 1976; Mann 1991). Following ionizing radiation sub‐acute or chronic intestinal damage develops gradually. In contrast to ARI, the histological changes in CRI are characterized by significant mucosal as well as submucosal changes. One of the cardinal features of CRI is endarteritis obliterans, which is characterized by the inflammation of the arteries‐particularly smaller arteries and degeneration of the intima, leading to the occlusion of blood vessels. The end result is ischemia, sub‐mucosal fibrosis and necrosis (Leadon 1996; Haimovitz‐Friedman 1998).

Several risk factors have been identified in the development of CRI. These are generally divided into treatment or patient related factors. Treatment related factors, such the volume of intestines radiated and the dose of radiation, tend to play a bigger role than patient related factors. At a radiation dose of 60 Gy, up to 50% of patients will be expected to develop CRI. Similarly the radiotherapy technique and concomitant chemotherapy may also influence the outcome. Commonly reported patient related factors include reduced body mass index, tobacco use, previous intestinal surgery, age and co‐morbidities such as diabetes, inflammatory bowel disease and hypertension (Carr 1994; Rodier 1995; Heemsbergen 2005; Fokdal 2005; Miller 2005; Morris 1999).

The degree of intestinal injury is influenced by the aforementioned factors and therefore the presentations vary. Up to 50% of patients are left with long term chronic gastrointestinal side effects, some of which may affect quality of life. The most frequently reported symptoms include diarrhea and constipation (Anseline 1981; Gami 2003). Although the cause of constipation, in this setting, is not clear, diarrhea is multifactorial. Bile salt malabsorption, small bowel bacterial overgrowth, accelerated small and large bowel transit, stricture formation, pancreatic insufficiency and fatty or carbohydrate malabsorption are some of the more commonly reported causes of diarrhea (Gami 2003; Andreyev 2005; Danielsson 1991; Ludgate 1985). Other, although less frequently reported, adverse effects of CRI include fecal incontinence, rectal bleeding, anemia, abdominal, perianal and back pain (Gami 2003; Putta 2005). Fistulas (recto‐vaginal, enteric, cutaneous) may be seen in as many as 5% of patients (Denton 2000; Nostrant 2000). Mucousy rectal discharge, urgency, rectal pain, and rectal stenosis are more bothersome symptoms observed in patients with radiation proctitis (Gami 2003). Rectal bleeding occurs from mucosal friability and neovascular telangiectasia, where as other symptoms may be due to decreased rectal compliance. These symptoms are most often classified according to the EORTC/RTOG (European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) score) grade for late gastrointestinal adverse effects (Cox 1995; Taylor 1993).

Grossly or on endoscopy, the presentation is variable. Based on the World Organization of  Digestive Endoscopy criteria,  Wachter 2000 developed the Vienna Rectoscopy Scoring system (VRS). This scoring system is based on the presence and the degree of five main alterations i.e. telangiectasias, congestion, ulceration, necrosis and stenosis within the rectum.

The true prevalence of chronic radiation enteritis is unknown, but may vary from 5 to 15% amongst radiotherapy recipients (Ooi 1999; Rodier 1995). Chronic radiation proctitis alone has been reported in 5 to 20% of patients whereas proctocolitis may be seen in 20% of patients post radiation therapy. These figures are, however, thought to be highly underestimated as not all patients with gastrointestinal symptoms due to radiotherapy seek medical care (Cho 1995; Muren 2005; Nichol 2005; Rancatti 2004; Wachter 2001).

Description of the intervention

Treatment and cure of CRI remains elusive. In spite of the recent developments in both prevention and treatment of radiation injury, the incidence as well the long term sequale of CRI remains high. While several pharmacological agents have been utilized, the evidence base for these therapies is generally poor and only a few high quality trials and comparisons between therapies exist. With no clearly defined management guidelines the outcomes are often unsatisfactory.

In addition to irreversible injury (e.g. fibrosis or fistulas ), the areas of radiation injury also tend not to heal and the outcomes even after endoscopic management are often disappointing (Cotti 2003). In fact some therapies may be dangerous as with argon plasma coagulation, which when used to ablate bleeding ischemic mucosa, may have a complication rate as high as 15% (Andreyev 2005). Surgical intervention is difficult to perform in light of the extension of fibrosis and alterations in the gut and mesentery and therefore conservative management is preferred. Surgical management is reserved for intestinal obstruction, perforation, fistulas, severe bleeding (Li 2006) and failure of medical treatment.

PREVENTION: Most advancements made in the prevention of radiation injury are non‐pharmacologic and include reducing the dosage of radiation (also known as intensity modulated radiotherapy) reducing the area of intestinal exposure to radiotherapy, multiple field arrangement and conformal radiotherapy techniques (three dimensional radiotherapy). These techniques have been relatively successful with a 25‐40% reduction in both acute and chronic gastrointestinal toxicity. Other non‐pharmacologic or physical measures include belly boards, surgical placement of an intestinal sling, bladder distention during treatment, insertion of absorbable mesh slings and breast prosthesis. These interventions are aimed at excluding the small bowel from the area of radiation, thereby reducing toxicity. Results are varied and where the absorbable mesh and the breast prosthesis have shown some promise, most other techniques and their results are not reproducible (Chen 1992; Cho 1995; Dasmahapatra 1991; Durig 1984; Gallagher 1986; Gaurd 1986; Heemsbergen 2005; Herbert 1993; Letschert 1990; Meric 1994; Rodier 1991; Sezeur 1999; Shanahan 1990; Waddell 1999).

Amongst the pharmacologic therapies, aminosalicylic acid derivatives, sucralfate preparations and nutritional therapies are the most studied. Pravastatin and simvastatin have been shown to protect against delayed enteropathy in rats (Haydont 2007) Similarly, teduglutide, a glucagon‐like‐peptide‐2 analogue, increases intestinal crypt stem cell survival in mice, when given before full body radiation (Booth 2004). Only a few controlled trials exist in humans.

TREATMENT: Even though there are no clear guidelines or recommendations for treatment of acute and chronic radiation injury, multiple treatment options; both pharmacologic and non‐pharmacologic are available. Amongst the non‐pharmacologic therapies the most effective may be endoscopic thermal coagulation therapies. These employ argon beam radiation, Nd:YAG laser or electrocoagulation. All three endoscopic techniques have been successful in the treatment of radiation proctitis, achieving a response in 66 to 100% of patients (Swaroop 1998; Taylor 1993). Other non‐pharmacologic techniques used include hyperbaric oxygen therapy. This has been shown to be effective because of its angiogenic effects. The mechanism of action is based on the decrease of tissue hypoxia with consequent acceleration of the healing process and restoration of local anti‐infectious defences (Warren 1997; Miura 1996; Myers 1998).

The evidence base for medical therapy of chronic radiation proctitis/enteritis is generally poor. Very few high quality trials and comparisons between therapies exist. Of the therapies which have been evaluated, sucralfate enemas, oral metronidazole and steroids enemas have shown some benefit.

How the intervention might work

• PREVENTION:

1. Aminosalysilic acid derivatives: Aminosalicylates include sulfasalazine and mesalamine and are administered orally or per‐rectum; as suppositories or enemas. These are anti‐inflammatory medications which work by a variety of mechanisms, including inhibition of prostaglandin synthesis, promotion of endogenous cytoprotective prostaglandins, inhibition of leukotriene  A4 to leukotriene B4 transformation, scavenging of oxygen radicals and alteration of bacterial flora. These agents have been used for the prevention of radiation injury including proctitis (Kilic 2000; Baughan 1993; Resbeut 1997; Jahraus 2005).

2. Sucralfate preparations: Sucralfate preparations may be given orally or in suspension enema forms. There are anti‐inflammatory agents which adhere to mucosal cells and exert their cytoprotective effects. They stimulate prostaglandin synthesis, promote local blood flow and increase the local production of epidermal growth factor. Sucralfate has been used for the prevention of proctocolitis (O' Brien 1997; Henriksson 1992).

3. Nutritional therapies: Nutritional therapies rich in glutamine, Arganine and Vitamin E have shown a protective effect on the intestinal mucosa in rats. Nutritional therapy has been evaluated as prevention therapy (Kozelsky 2003; Jenson 1994).

4. Probiotics: Probiotics are live micro‐organisms that, when administered in adequate amounts may confer a health benefit to the host. The role of probiotics has been evaluated in the prevention of radiation induced diarrhea (Delia 2002; Salminen 1988).

5. Misoprostol: Misoprostol is a prostaglandin E1 analogue, which has cytoprotective effects and works by promoting mucosal blood flow. Misoprostol rectal suppositories may be useful for the prevention of acute and chronic symptoms of radiation proctopathy (Khan 2000).

• TREATMENT:

1. Sucralfate preparations: Sucralfate has been used for the treatment of post‐radiation induced proctocolitis and has been shown to induce remission in most patients presenting with moderate to severe rectal hemorrhage (O' Brien 1997; Sasai 1998; Oliveria 1998; Kochhar 1999; Henriksson 1992; Kneebone 2004).

2. Corticosteroids: Corticosteroids are available in oral, rectal and IV forms. These anti‐inflammatory medications have a wide range of metabolic and physiological effects, and may act by inhibiting the arachidonic acid cascade, blocking cytokine release and production, inhibiting histamine release and stabilizing cell membranes. Corticosteroids have been used for the treatment of radiation enteritis, colitis and proctitis by reducing the radiation induced inflammatory response (Kochhar 1999; Loiudice 1983).

3. Aminosalicylic acid derivatives: These agents are used for the treatment of radiation enteritis, colitis and proctitis and reduce the radiation induced inflammatory response. Studies have reported clinical (symptom improvement) and radiologic improvement in patients with radiation procto‐sigmoiditis (Bondesen 1987; Freund 1987; Baum 1989; Kilic 2000; Baughan 1993; Resbeut 1997; Goldstein 1976).

4. Estrogen/progesterone: Estogen and progesterone are given orally. These are hormones which may be employed in the treatment of radiation induced bleeding/radiation proctitis (Niv 1995; Van Cutsem 1990; Van Cutsem 1993).

5. Short chain fatty acid enemas: Short chain fatty acids (SCFA) are the main energy source of colonocytes. They provide nutrients directly to the colonocytes in order to accelerate tissue repair and are produced within the colon, predominantly by anaerobic bacterial fermentation of non‐absorbable carbohydrates, which are delivered by the dietary fiber component. Their use may be impaired in chronic radiation proctitis and colitis. Butyrate is the most commonly used SCF agent (Pinto 1999; Vernia 2000).

6. Formalin. Formalin is a solution of formaldehyde gas (10% formalin, 3.7% formaldehyde solution, 1.2% methanol) Formalin has been used as for treating refractory radiation‐induced hemorrhagic proctitis. It is administered via a sigmoidoscope/proctoscope. Gauze or a cotton tip applicator, soaked in 4% formalin, is applied under direct visualization to the hemorrhagic telangiectasias, until the bleeding ceases (Pikarsky 2000; Shrom 1976; Myers 1998; Rubenstein 1986; Biswal 1995; Seow‐Choen 1993; Counter 1999; Saclarides 1996).

7. Anti‐Diarrheals: Anti‐motility agents such as loperamide, codeine phosphate and lamotil have been evaluated for diarrhea associated with radiation enteritis. These agents may improve diarrhea by improving intestinal transit times and by increasing bile salt absorption (O' Brien 1988; Waller 2001; Sun 1997; Yeoh 1993).

8. Antibiotics: Antibiotics such as metronidazole and doxycycline have been evaluated in patients with radiation enteritis. As bacterial overgrowth is common with radiation enteritis, antibiotics may be useful adjunct medications for reducing symptoms, such as diarrhea and bloating (Andreyev 2005; Danielsson 1991).

9. Cholestyramine: Cholestyramine is a bile salt resin (binder). Cholestyramine has been evaluated in the treatment of bile acid mal‐absorption, which  is responsible for diarrhea in 35 to 72% of patients with chronic radiation enteritis (Andreyev 2005; Danielsson 1991; Arlow 1987; Kamal‐Bahl 2007).

10. Pentoxyfylline and Tocopherol: The principle change seen in radiation induced injury is fibrosis. It has been suggested that anti‐fibrotic agents such as pentoxifylline and tocopherol in combination with symptomatic therapy may produce better outcomes. These medications may abrogate radiation‐induced fibrosis through antioxidant effects (Hille 2005; Gothard 2005; Chiao 2005).

11. Nutritional therapy: Studies have suggested that elemental or exclusion diet (e.g. lactose free diet) may be beneficial for the treatment of radiation enteritis. Intestinal rest using parenteral nutrition has also been assessed in patients with chronic radiation enteritis. An improvement in nitrogen balance as well as clinical and radiological findings has been noted in patients with small bowel radiation injury treated with total parenteral nutrition compared with those treated with an elemental feed (Loiudice 1983; Donaldson 1975; Gavazzi 2006; Scolapio 2002; Silvain 1992; Salminen 1988).

12. Probiotics: These are live microorganisms thought to be important for the host immunity and gut function. Radiation therapy may lead to changes in the intestinal flora thereby affecting the gut motility and the intestinal permeability.  The resulting diarrhea has been shown to respond to probiotics such as Lactobacillus acidophilus (Salminen 1988).

13. Octreotide: Octreotide is a somatostatin analogue. Amongst its many actions including inhibition of hormonal secretion, it may also reduce secretion of fluids by the intestine and reduce gastrointestinal motility.  It has been shown to be highly effective for the control of diarrhea associated with certain chemotherapeutic agents, with bone marrow transplantation and in patients with hormone producing tumors. Octreotide administration may effectively reduce acute mucosal changes after irradiation of small bowel because of its multiple, mainly inhibitory, effects in the gastrointestinal tract, including potent inhibition of exocrine pancreatic secretion. Other actions include strong inhibitory effects on gastrointestinal secretions and hormones, the gastrointestinal motility, blood flow, and epithelial cell proliferation (Morris 1993; Wang 1999; Guan 1990; Lamberts 1986; Dharmsathaphorn 1980; Lembcke 1987).

14. Vitamin A: Vitamin A or oral retinol palmitate have wound healing properties and have been evaluated for treating rectal symptoms of radiation proctopathy. A significant improvement in rectal symptoms has been reported in these trials (Ehrenpreis 2005; Beyzadeoglu 1997).

Why it is important to do this review

The number of cancer survivors in the United States has tripled in the last three decades of which at least half have received radiotherapy as part of their treatment (Bentzen 2006; Hauer‐Jensen 2003). Radiation is associated with significant mortality and morbidity due to its injurious effects on adjacent tissues, mainly the colon and the small intestines. In addition to the presenting symptoms of acute and chronic radiation colitis and enteritis, chronic radiation injury may be associated with serious long term manifestations including fistulas, perforations, strictures, sepsis and cancer (Tamai 1999; Narui 2006). Effective therapeutic strategies are therefore needed to prevent and manage this disease. Although multiple therapeutic regimens have been suggested, there are no clear guidelines for the treatment and prevention of radiation colitis, enteritis and proctitis.

This review will attempt to identify all the randomized controlled trails available for the treatment and prevention of radiation induced injury and will make an effort to suggest a more evidence based approach.

Objectives

The aim of the study is to assess the efficacy of different pharmacological therapies for the treatment and prevention of radiation colitis, enteritis and proctitis in patients who are past recipients of radiation therapy.

Methods

Criteria for considering studies for this review

Types of studies

The systemic review will include studies that have met the following criteria:

1. Randomized controlled trials (RCT's). Studies which were described as randomized by the authors.

Types of participants

Patients who fulfil the following criteria will be considered for inclusion:

1. All patients must be older than 18;

2. All patients must have abdominal or pelvic malignancies;

3. All patients must have received radiation therapy as part of their treatment schedule. The radiation therapy may have been given as the primary therapy, post‐operatively, with or with out chemotherapy;

4. Patients may have subsequently developed symptoms suggestive of radiation induced injury for example, diarrhea, bleeding, weight loss, malabsorption, urgency, tenesmus or incontinence; and

5. Patients may have presented during or up to 30 years after radiation therapy

Types of interventions

The following pharmacological treatments have been used for the treatment and prevention of radiation induced enteritis, proctitis and colitis:

1. Sucralfate preparations;

2. Short chain fatty acid enemas;

3. Corticosteroids;

4. Anti‐Diarrheals;

5. Amino‐salicylic acid derivative;

6. Antibiotics;

7. Formalin;

8. Pentoxypyline and tocopherol;

9. Probiotics;

10. Cholestyramine;

11. Nutritinal therapy;

12. Misoprostol;

13. Estrogen/Progesteron;

14. Octreotide; and

15. Vitamin A.

All studies will be included which involved a trial of any of these agents. All routes of administration will be included.

Types of outcome measures

Primary outcomes

The primary outcome for treatment interventions will be the proportion of patients with clinical improvement as defined by the included studies (e.g. rectal bleeding, diarrhea, tenesmus, urgency, abdominal pain, incontinence and weight loss) and expressed as a percentage of the number of patients randomized (intention to treat analysis).

The primary outcome for prevention interventions will be the proportion of patients who develop radiation colitis, enteritis or proctitis as defined by the included studies and expressed as a percentage of the number of patients randomized (intention to treat analysis).

Secondary outcomes

Secondary outcome measure will include improvement in quality of life, any adverse events associated with the medications, cost effectiveness (hospitalizations, number of procedures) and mortality.

Search methods for identification of studies

For our electronic searches the following key words will be used:

2. Key words:

• Radiation treatment and it's synonyms.

• Enteritis, colitis, proctitis, and proctopathy and their synonyms.

• Upper and lower gastrointestinal symptoms.

• The three searches will be combined with the Boolean Operator "AND"

Electronic searches

The time frame used for searches will be from 1966 to November 2010. The search will be performed using a combination of MeSH headings and free text. A search strategy will be developed for Medline and modified for different databases. All relevant articles will be retrieved and the inclusion criteria will be applied to all before their inclusion in the systemic review.

The following electronic data bases will be searched:

1. Cochrane Central Register of Controlled Trials

2. PubMed: 1966 to November 2010

3. EMBASE: 1980 to November 2010

4. Science citation index: 1991 to November 2010.

5. Digestive Disease Week: 1980 to 2010

6. CENTRAL: no limits

7. IBD/FBD SR: no limits

Searching other resources

1. Gastroenterology conference proceeding for abstracts; including Digestive Disease Week (DDW) and the Cochrane IBD/FBD group specialized trials register (IBD/FBD SR)

2. Hand searching

3. Review of reference lists of selected studies and textbooks.

Data collection and analysis

Selection of studies

Two review authors (SA and IH) will scan all the applicable titles and abstracts. Full text for all the potentially relevant studies will be retrieved. Decisions about selection of studies will be made through discussion and consensus amongst the authors. In the case of discordance, resolution will be sought by discussion.

Data extraction and management

Two authors (SA and IH) will independently extract data from the studies and enter the following data into Review Manager Software.

Extracted data will include the following items:

1. Population: Mean age, gender, number of subjects; the type of underlying malignancy, the grade of radiation proctitis, colitis and enteritis before treatment and any additional therapeutic measures including chemotherapy or surgery. Data will also be collected on the radiation dose and the location of radiation therapy. Presenting symptoms of patients and length of follow‐up will also be recorded.

2. Intervention: The different types of medication used for treatment, the mode of administration (PO, PR or IV) their dosage and frequency will be recorded.

3. Adverse effects: All adverse effects associated with the medications will be recorded.

4. Design: Trial quality characteristics will be collected.

5. Potential confounding factors: We will perform assessment of previous treatment or any additional procedures performed on patients.

Any disagreements about the data extraction process will be resolved by referring back to the original article and by discussion and consensus amongst authors. Where necessary, information will be sought from the authors of the primary study for clarification of the missing information.

Assessment of risk of bias in included studies

All the studies which meet the inclusion criteria will be selected. All authors will independently assess the risk of bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Factors assess will include:

1. Sequence generation (i.e. is the allocation sequence adequately generated?);

2. Allocation sequence concealment (i.e. is allocation adequately concealed?);

3. Blinding (i.e. is the knowledge of the allocated intervention adequately prevented during the study?);

4. Incomplete outcome data (i.e. is incomplete outcome data adequately addressed?);

5. Selective outcome reporting (i.e. are reports of the study free of suggestion of selective outcome reporting?)

6. Other potential sources of bias (i.e. is the study apparently free of other problems that could put it at a high risk of bias?).

A judgement of 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates unclear or unknown risk of bias. Disagreements will be resolved by consensus. Study authors will be contacted when insufficient information is provided to determine risk of bias.

Measures of treatment effect

For dichotomous outcomes (clinical improvement ) results will be expressed as relative risk (RR) with 95% confidence intervals (CI).

For continuous outcomes (symptom scores and QoL) results will be converted to weighted mean differences and an overall weighted mean difference (WMD) will be calculated with 95% CI .

Dealing with missing data

For any missing data, where possible, the study authors will be contacted either by electronic mail or phone. The studies where data for a particular outcome cannot be identified or obtained from the author will not be included for analysis of that outcome.

Assessment of heterogeneity

The presence of heterogeneity among studies will be assessed using the chi‐square test (a P value of 0.10 will be regarded as statistically significant). The I² measure will be calculated to quantify inconsistency. The I² measure describes the percentage of total variation across studies that is due to heterogeneity rather than chance, and can be interpreted as follows: 25% ‐ low heterogeneity, 50% ‐ moderate heterogeneity, 75% ‐ high heterogeneity (Higgins 2003).

Data synthesis

Data will be pooled for analysis if the patients, treatments and outcomes are sufficiently similar. Data will not be pooled if there is a large amount of unexplained heterogeneity (e.g. I²  > 75%).

Sensitivity analysis

Sensitivity analyses will be conducted based on the following: study quality (quality of allocation concealment) year of publication, type of outcome measures and random and fixed effects models if appropriate.

What's new

Date	Event	Description
29 March 2017	Amended	This protocol is being withdrawn. The author team does not have the time and resources to complete the review.

Contributions of authors

Sobia Ali will write the protocol and the review with help from the other author. Sobia Ali and Ihtasham Habib will review the titles and abstract separately and then they both will select studies to be included.

Declarations of interest

The authors have no declaration of interest.

Notes

This protocol is being withdrawn. The author team does not have the time and resources to complete the review.

Withdrawn from publication for reasons stated in the review