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Cochrane Database of Systematic Reviews Protocol - Intervention

Oral water soluble contrast for malignant bowel obstruction

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Abstract

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

To determine the reliability of oral water soluble contrast media and follow up abdominal radiographs in predicting the success of conservative treatment in resolving inoperable malignant bowel obstructions with conservative management.

To determine the efficacy and safety of oral water soluble contrast media in reducing the duration of obstruction and reducing hospital stay in people with malignant bowel obstruction.

Background

Description of the condition

Bowel obstruction refers to any mechanical or functional obstruction of the intestine that prevents physiological transit and digestion (Tuca 2012). For the purposes of research, malignant bowel obstruction (MBO) has been defined using the following criteria (Anthony 2007).

  1. That the patient has clear clinical evidence of a bowel obstruction (based on history, examination and radiological criteria), and

  2. That the bowel obstruction be located distal to the Ligament of Treitz (at the junction of the duodenum and jejunum), and either

  3. That the patient has an intra‐abdominal primary cancer with incurable disease, or

  4. That the patient has a non intra‐abdominal primary cancer with clear intra‐peritoneal disease.

MBO is reported to have a prevalence of 3% to 15% in cancer patients (Tuca 2012). Its symptoms, such as nausea, vomiting, abdominal pain and distension, can cause significant physical distress. MBO is common in patients with ovarian cancer (20% to 50% of ovarian cancer patients present with symptoms of bowel obstruction) and colorectal cancer (10% to 28% developing an obstruction through the course of their disease) (Ripamonti 2008). Breast cancer and melanoma are the most common extra‐abdominal cancers associated with MBO (Ripamonti 2008).

MBO may be directly related to intra‐abdominal tumour growth causing extrinsic compression of the bowel, intraluminal obstruction or by intramural infiltration (Tuca 2012). In patients with cancer, bowel obstructions may also be caused by post‐surgical adhesions or radiation fibrosis. Intestinal motility disorders leading to obstruction may be caused by direct infiltration by cancer of the coeliac plexus, mesentery, bowel wall or nerves. Intestinal dysmotility may also be caused by paraneoplastic syndromes or opioid‐related constipation. Obstruction may be partial or complete, may occur in the small or large bowel, and may occur singularly or at multiple levels.

Bowel obstruction may be diagnosed with plain abdominal x rays showing distension of the intestinal loops, the presence of air‐fluid levels in the zone proximal to the occlusion as well as a reduction in gas and stools in the segments distal to the obstruction. Computed tomography (CT) scans or magnetic resonance imaging (MRI) provide better sensitivity and specificity in diagnosing the level of obstruction, in addition to providing information on other sites of metastatic disease that may influence management decisions. Where curative surgery is not possible, palliative surgery or endoscopic stenting may be appropriate management for patients with suitable sites of disease, performance status and prognosis. In other patients whose disease is considered inoperable, palliation of symptoms is performed until either the obstruction resolves or the patient dies.

Spontaneous resolution of an inoperable bowel obstruction may occur in approximately one third of cases (Tuca 2012). In a prospective cohort study the mean survival was “12 days (95% CI = 9.0 – 14.1) for patients with no spontaneous resolution of their malignant bowel obstruction, and 57 days for patients with complete resolution, (P < 0.001)” (Tuca 2012). There is also a suggestion that early and aggressive medical management of an MBO may induce resolution and prevent the obstruction from becoming irreversible (Mercadante 2004). There appears to be little evidence to determine which MBOs are likely to resolve with conservative management (i.e. spontaneously or with medical management).

Description of the intervention

Oral water soluble contrast (OWSC) is an iodinated contrast medium that shows up opaque on plain X‐ray. The most common form used is gastrografin ‐ a hyperosmolar solution that is a combination of sodium diatrizoate and meglumine diatrizoate.

A previous Cochrane review assessed the benefit of OWSC for adhesive bowel obstruction (Abbas 2007). OWSC was administered either orally or via a nasogastric tube with an abdominal X‐ray taken at a set time afterwards. It showed that OWSC in the colon on an abdominal X‐ray within 24 hours was highly predictive of resolution of adhesive small bowel obstruction. However the use of OWSC did not decrease the need for surgical intervention, but did decrease hospital stay. In this review we will search for studies using the same or a similar intervention to attempt to predict the likelihood of malignant small bowel obstruction resolving with conservative management. That is, does OWSC reaching the colon in a patient with malignant small bowel obstruction indicate with an acceptable sensitivity and specificity that the obstruction will resolve with conservative or medical treatment alone? This will be the diagnostic arm of the review.

Administration of water soluble contrast (in most studies, 100mLs of gastrografin) was tested as a therapeutic agent in adhesive bowel obstruction (Abbas 2007). This review will once again search for studies with similar interventions to treat MBO (small bowel obstruction or inoperable large bowel obstruction). This will be the therapeutic arm of the review.

Although the potential adverse effects of using OWSC include vomiting, diarrhoea, hypersensitivity reactions and rarely bowel perforation or aspiration pneumonia, the Cochrane review into its use in adhesive small bowel obstruction concluded that it was safe in that setting, as there was no increase in morbidity or mortality through its use in the reported studies (Abbas 2007).

How the intervention might work

OWSC agents are generally felt to be more useful than barium for imaging in small bowel obstructions, as they promote peristalsis and are less irritating to the peritoneum in the event of a perforation (Joyce 1992; Mercadante 2004; Riccabona 2014). The hyperosmolar nature of OWSCA is thought to attract fluid from the bowel wall into the lumen, potentially assisting to resolve the obstruction by decreasing oedema in the bowel wall (Khasawneh 2013). By shifting fluid into the bowel lumen, it also increases the pressure gradient across an obstructive site and, as the bowel content is also diluted, this may assist its movement through a narrower or partially‐obstructed lumen (Mercadante 2004; Vather 2015).

Why it is important to do this review

Published literature suggests that gastrografin may be of benefit in the management of reversible MBOs (Ripamonti 2001; Ripamonti 2002; Mercadante 2004; Ripamonti 2008; Khasawneh 2013). However it is not clear what level of evidence supports this recommendation. Also, while there is evidence that gastrografin assists in predicting which adhesive bowel obstructions may resolve with conservative management (Abbas 2007), it is not clear whether this also applies to MBO, given the large number of other possible causes (extrinsic compression, intraluminal narrowing, etc). In this review we seek to identify whether the use of OWSC is able to identify patients with inoperable malignant small bowel obstruction in whom the obstruction is likely to resolve with conservative management. This may be important in judging the patients' prognoses and influence their planning for end‐of‐life care. We will also seek evidence as to whether water soluble contrast has a therapeutic role in the reversal of MBO at any level, which may reduce morbidity and the duration of hospital stay for patients undergoing palliative care. If the administration of OWSC is able to prevent the obstruction from becoming irreversible, then this may also improve survival time from the onset of the obstruction until death.

Objectives

To determine the reliability of oral water soluble contrast media and follow up abdominal radiographs in predicting the success of conservative treatment in resolving inoperable malignant bowel obstructions with conservative management.

To determine the efficacy and safety of oral water soluble contrast media in reducing the duration of obstruction and reducing hospital stay in people with malignant bowel obstruction.

Methods

Criteria for considering studies for this review

Types of studies

We will review prospective studies to evaluate the diagnostic potential of oral water soluble contrast (OWSC) in predicting which malignant small bowel obstructions will resolve with conservative treatment.

To review the therapeutic potential of OWSC in managing malignant bowel obstruction (MBO) at any level we will look at randomised controlled trials. If no randomised controlled trials are found, relevant prospective controlled studies will be discussed but not included in a meta‐analysis.

Types of participants

Adult patients (aged 18 and over) who meet the criteria for MBO as listed above where the obstruction is limited to the small bowel only (diagnostic).

Adult patients (aged 18 and over) who meet the criteria for MBO listed above and where surgery or endoscopic stenting are not appropriate, or with malignant small bowel obstruction who are having a trial of conservative management before a decision on surgery/stenting is made (therapeutic).

Types of interventions

  1. The administration of oral water soluble contrast (OWSC) in patients with the diagnosis of malignant small bowel obstruction followed by interval abdominal radiographs to identify contrast in the colon (diagnostic).

  2. The administration of OWSC to patients with MBO to assess its ability to resolve the obstruction.

Comparison:

  • Placebo;

  • No intervention;

  • Usual treatment or supportive care.

Types of outcome measures

We will include a 'Summary of findings' table as set out in the PaPaS author guide (AUREF 2012) and recommended in the Cochrane Handbook, chapter 4.6.6 (Higgins 2011). The 'Summary of findings' table will include the primary and secondary outcomes listed below. For each outcome, the overall quality of the evidence will be assessed using the GRADE system (GRADEpro 2015) and also presented in the 'Summary of findings' table. The assessment will be focused on the quality of available evidence, the magnitude of the effect of using OWSC and the sum of available data on the main outcomes. See Appendix 1 for a further description of the GRADE system.

Primary outcomes

  1. The ability of OWSC, when seen to reach the colon on follow‐up imaging, to predict the likelihood of malignant small bowel obstruction resolving with conservative treatment alone (diagnostic).

  2. The rate of resolution of MBO with medical management only in patients receiving OWSC compared with those not receiving it (therapeutic).

  3. Gastrointestinal adverse effects (increased abdominal pain, nausea, vomiting).

  4. Extra‐abdominal complications (aspiration pneumonia, hypersensitivity reactions).

Secondary outcomes

  1. Length of hospital stay.

  2. Time from administration of OWSC to resolution of MBO.

  3. Survival time from onset of inoperable MBO until death.

Search methods for identification of studies

The search strategy will not be limited by language, publication type or status, or by date.

Electronic searches

We will search the following electronic databases:

  1. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library);

  2. MEDLINE (Ovid);

  3. EMBASE (Ovid);

  4. CINAHL;

  5. Science Citation Index (Web of Science);

  6. Conference Proceedings Citation Index ‐ Science (Web of Science).

Medical subject headings (MeSH) or equivalent and text word terms will be used. The search strategy for MEDLINE (Ovid) can be seen in Appendix 2. The MEDLINE search strategy suggested by the main author was revised and adapted by the Trials Search Coordinator of the Cochrane Pain, Palliative and Supportive Care Review Group. The Cochrane Highly Sensitive Search Strategy filter for identifying randomised trials in MEDLINE via Ovid (Lefebvre 2008) was also applied. This search will be adapted and modified across the other databases.

Searching other resources

The bibliographic references of any relevant identified studies will be checked in order to find additional trials not identified by the electronic searches. We will also search clinicaltrials.gov (www.Clinicaltrials.gov), the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com/mrct/), and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/) to identify any ongoing trials. For grey literature, we will search the Internet using the Google scholar search engine (www.googlescholar.com) and CareSearch Grey Literature databases (http://www.caresearch.com.au) with selected terms from the above strategy.

If only abstracts are identified and no full‐text paper can be retrieved, the study authors will be contacted for further details. We will also attempt to contact authors in the case of incomplete data sets.

The searches will be conducted by the Trials Search Coordinator of the Cochrane Pain, Palliative and Supportive Care Review Group.

Data collection and analysis

Selection of studies

All titles and abstracts of the studies identified by the searches will be independently assessed by at least two of the review authors. Each of these authors will independently select all potentially‐relevant studies by applying the selection criteria outlined in the Criteria for considering studies for this review. Studies meeting the criteria will be included in the review irrespective of whether measured outcome data are reported in a 'usable way'. The authors' selections will then be compared, and any differences discussed and the papers either included or excluded based on a majority decision.

A PRISMA study flow diagram (Liberati 2009) will be included in the full review to document the screening process, as recommended in Part 2, Section 11.2.1 of the Cochrane Handbook (Higgins 2011).

Data extraction and management

For each study at least two review authors will independently extract data using a piloted data extraction form. Data extracted will include information about the year of study, study design, number of participants treated, participant demographic details, type of cancer, drug and dosing regimen, study design (placebo or active control) and methods, study duration and follow‐up, outcome measures (reduction in duration of obstruction, length of stay, likelihood of resolution if contrast reaches colon), withdrawals and adverse events. In studies with more than two intervention arms, this review will only include the intervention and control groups that meet the eligibility criteria. Multi‐arm studies included in the review will have their multiple intervention groups analysed in an appropriate way to avoid arbitrary omission of relevant groups and double‐counting of participants. We will resolve potential disagreements by discussion and majority decision.

Assessment of risk of bias in included studies

The studies will be divided among the author group so that two authors will independently assess the risk of bias for each study. This will be done using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion. We will complete a 'Risk of bias' table for each included study using the 'Risk of bias' tool in RevMan (RevMan 2014). We will assess the following for each study.

Random sequence generation (checking for possible selection bias). We will assess the method used to generate the allocation sequence as: low risk of bias (any truly random process, e.g. random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). Studies using a non‐random process (e.g. odd or even date of birth; hospital or clinic record number) will be deemed to be at high risk of bias and excluded.

Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We will assess the methods as: low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). Studies that do not conceal allocation (e.g. open list, date of birth or any other explicitly unconcealed procedure) will be deemed to be at high risk of bias and excluded.

Blinding of participants, personnel (checking for possible performance bias). We will assess studies as low risk of bias if they adequately describe how the blinding of key study participants and personnel has been assured. Studies will be assessed as high risk of bias if there was no blinding or incomplete blinding which may impact on the assessment of adverse effects from OWSC. An assessment of unclear risk of bias will apply to studies where there is insufficient information to permit judgement of 'high' or 'low' risk.

Blinding of outcome assessment (checking for possible detection bias). We will assess the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We will assess the methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, e.g. identical tablets; matched in appearance and smell); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved). Studies where there was no blinding of outcome assessment or where the blinding may have been broken which may affect outcome measurements (particularly adverse effects of OWSC) will be deemed high risk of bias and excluded.

Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data). We will assess the methods used to deal with incomplete data as: low risk (< 10% of participants did not complete the study and/or used ‘baseline observation carried forward’ analysis); unclear risk of bias (used 'last observation carried forward' analysis); or high risk of bias (used 'completer' analysis).

Selective reporting (checking for reporting bias). We will assess studies as being at low risk of bias (all of the relevant pre‐specified outcomes listed in the protocol and reported in the pre‐specified way); high risk of bias (one or more outcomes of interest are reported incompletely so that they cannot be entered in a meta‐analysis); or unclear risk of bias (insufficient information to permit judgement of 'high risk' or 'low risk').

Size of study (checking for possible biases confounded by small size). We will assess studies as being at low risk of bias (≥ 200 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); or high risk of bias (<50 participants per treatment arm).

Measures of treatment effect

For dichotomous outcomes between groups, we will estimate and compare the risk ratio (RR) using a 95% confidence interval (CI). For continuous outcomes between groups, we will measure arithmetic means and standard deviation (SD) and will report the mean difference (MD) with 95% CI. When an outcome is derived with different instruments measuring the same construct, we will use standardised mean difference (SMD) with 95% CI.

For unwanted effects, we will calculate the numbers needed to treat to harm (NNH) using dichotomous data to calculate RR with 95% CI. We will use the following terms to describe adverse outcomes in terms of harm or prevention of harm:

  • When significantly fewer adverse outcomes occurred with oral water soluble contrast than with control (placebo or active) we will use the term 'number needed to treat to prevent one event' (NNTp).

  • When significantly more adverse outcomes occurred with water soluble contrast compared with control (placebo or active) we will use the term 'number needed to harm or cause one event' (NNH).

Unit of analysis issues

We will only include studies in which randomisation is by the individual patient; this will include cross‐over or n = 1 studies.

Dealing with missing data

In cases where data are missing, we will contact the authors to request the missing data. Intention‐to‐treat (ITT) analysis will be used. Missing participants or information will be assigned to a zero improvement category where possible. The method of assessing data processed from withdrawals will be ascertained where possible. Where there are substantial numbers (> 10%) of participants missing from analyses, we will perform sensitivity analyses.

Assessment of heterogeneity

We will undertake a meta‐analysis only if participants, interventions, comparisons and outcomes are judged to be sufficiently similar to ensure an answer that is clinically meaningful. There may be an effect of differences between patients, level of obstruction (small bowel versus large bowel) and outcome measures. We will assess heterogeneity by using the I2 statistic. We will consider I2 values above 50% to represent substantial heterogeneity in line with Higgins 2011, and will assess potential sources of heterogeneity through subgroup analyses.

Assessment of reporting biases

If there are at least 10 studies in the meta‐analysis we will assess the likelihood of publication bias by examining funnel plot symmetry to interpret the results of statistical analysis. If there is evidence of small study effects, we will consider publication bias as only one of a number of possible explanations (Higgins 2011).

Data synthesis

We will enter the data extracted from the included studies into Review Manager software (RevMan 2014) which will be used for data synthesis. Where appropriate, we will pool data for each dichotomous outcome and calculate risk ratios with 95% CI using the fixed‐effect model, together with numbers needed to treat for an additional beneficial outcome (NNTBs) with 95% CIs and, for adverse events, numbers needed to treat for an additional harmful outcome (NNTHs) with 95% CIs.

Subgroup analysis and investigation of heterogeneity

If sufficient data are available, we will perform the following subgroup analyses:

  1. Level of obstruction (small bowel or large bowel)

  2. Degree of obstruction (partial or complete)

  3. Dose of OWSC used

  4. Timing of follow‐up abdominal x ray (diagnostic)

  5. Type of cancer

Sensitivity analysis

When sufficient data are available, we will examine the robustness of the meta‐analyses by conducting sensitivity analyses using different components of the 'Risk of bias' assessment, particularly those relating to whether allocation concealment and patient/assessor blinding were adequate. We will conduct further sensitivity analyses to examine the impact of missing data on the results as a large proportion of the studies are at an ‘unknown’ or ‘high risk’ of attrition bias, and finally, to examine whether publication status and trial size influenced the results.