Description of the condition
Patients with head and neck cancer have a high incidence of postoperative complications, including major wound infections, fistula formation, septicaemia and pneumonia. Many are malnourished because of mechanical obstruction, tumour-induced cachexia, poor dietary habits and excessive alcohol consumption. Poor nutrition is known to have an adverse impact on outcome in this patient group (van Bokhorst 2000). These patients have well documented immune defects including T-lymphocytopenia and dysfunction, and reduced monocyte HLA-DR expression; they also have reduced prostaglandin concentration and antigen-antibody complexes (Hadden 1997). These defects, combined with the immune suppressive effects of surgery, contribute to increased postoperative complications, such as poor wound healing and sepsis.
Description of the intervention
There is evidence that giving patients perioperative nutritional supplements with immunonutritional additives can favourably modulate the immune and inflammatory response both in vitro and in patients with trauma, burns or those undergoing gastrointestinal surgery (Di Carlo 1999; Wu 2001). Meta-analysis suggests that immunonutrition reduces infectious complications in critically ill patients (Heyland 2001). Standard commercial nutritional supplements are described as polymeric, which means they contain whole protein, partially digested starch and triglycerides with electrolytes, minerals and trace elements, haematinics and vitamins. They are usually given in liquid form and are designed to provide a patient's 'complete' nutritional requirements, provided they are given in an appropriate volume. Immunonutrition and standardised commercial nutrition supplements may be given either orally or via an enteral feeding tube. Any form of early enteral feeding carries a risk of aspiration; this is not specific to enteral immunonutrition.
How the intervention might work
The most studied immunonutrition nutrients used are arginine, glutamine, omega-3 fatty acids and nucleotides. Arginine is the most common immunonutrient given to patients with head and neck cancer. It is a non-essential amino acid with a role in the synthesis of nucleotides, polyamines, nitric oxide and proline. Arginine stimulates lymphocyte function and improves wound healing. The content of each immunonutrition formula varies between products.
Why it is important to do this review
Studies of head and neck cancer patients receiving immunonutrition in the perioperative period have not conclusively demonstrated benefit (Stableforth 2009). We carried out a systematic review of randomised controlled trials in 2009 to determine whether perioperative immunonutrition has a role in the treatment of head and neck cancer (Stableforth 2009). In this review we examined 10 trials investigating the effects of immunonutrition in patients treated surgically for head and neck cancer. A reduction in the length of postoperative hospital stay was seen, but the reason for this reduction was not clear (Figure 1). Most trials were too small to provide precise estimates of intervention effects. There were insufficient data to exclude substantial effects of immunonutrition on clinical outcomes or biochemical and immunological parameters. Since the publication of this review in 2009 there have been further studies identified which merit evaluation and inclusion in an updated review (Buijs 2010; De Luis 2009; De Luis 2010; Felekis 2010; Sorensen 2009). Cochrane methodology will enable a full and balanced review of the literature.
|Figure 1. Length of hospital stay.|
To assess the effects of immunonutrition treatment, compared to standard feeding, on postoperative recovery in adult patients undergoing elective head and neck surgery.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs). We will include quasi-randomised trials but these will be subject to a sensitivity analysis. We will include studies irrespective of language and publication status.
We will exclude non-randomised studies, such as cohort studies, because of the increased potential for bias. We will also exclude cross-over trials as this methodology is not suitable for evaluating an intervention that must be given at a specific time point.
Types of participants
We will include all adult patients (18 years of age or older) undergoing an elective surgical procedure for head and neck surgery for cancer under a general anaesthetic.
Types of interventions
The intervention will be polymeric nutritional supplements with immunonutritional additives given by an enteral route. In order to be included, studies will need to plan to administer the immunonutrition preoperatively, postoperatively or both pre- and postoperatively. Co-intervention with other oral or parenteral substances will be permitted as long as the dose of immunonutritional additives is quantified. The content of each immunonutrition formula varies between products and we will record the product used and its contents for each study.
The control group will receive either traditional care (intravenous fluids) or polymeric nutritional supplements.
Types of outcome measures
- Length of hospital stay: measured in days
- Wound infections and/or fistula formation
- Adverse events
We will assess the following secondary outcomes, measured postoperatively:
- All-cause mortality
- Postoperative complications, as defined by trial authors
- Biochemical changes, as defined by trial authors
- Immunological changes, as defined by trial authors
Search methods for identification of studies
We will conduct systematic searches for randomised controlled trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear, and we will arrange translations of papers where necessary.
We will identify published, unpublished and ongoing studies by searching the following databases from their inception: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library); PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; ISRCTN; ClinicalTrials.gov; ICTRP, Google Scholar and Google.
We will model subject strategies for databases on the search strategy designed for CENTRAL (Appendix 1). Where appropriate, we will combine subject strategies with adaptations of the highly sensitive search strategy designed by The Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)).
Searching other resources
We will scan the reference lists of identified publications for additional trials and contact trial authors if necessary. We will search PubMed, TRIPdatabase, The Cochrane Library and Google to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. We will search for conference abstracts using the Cochrane Ear, Nose and Throat Disorders Group Trials Register.
Data collection and analysis
Selection of studies
We will combine the results of the searches above and exclude duplicate records. Two authors will independently screen all titles and abstracts for eligibility (NH and ST). We will not be blinded to any details of the published studies. We will independently record the reasons for study exclusion. Disagreements over study selection will be resolved by discussion and the third author (SL) will arbitrate. We will contact trial investigators if further information is required. We will compile a list of all eligible studies.
Data extraction and management
Two authors (NH and ST) will independently extract and collate data on a paper pro-forma. We will resolve any inconsistencies between extracted data by discussion. A consensus view will be reached following discussion with the third author (SL). If further information is required from a study, NH will contact the nominated trial investigator.
Assessment of risk of bias in included studies
Two authors will independently assess the risk of bias of the eligible studies (NH and ST). We will resolve disagreements by discussion and consensus, in which the third author (SL) will arbitrate. We will perform assessment of risk of bias using the 'Risk of bias' tool described in Chapter 8 of theCochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).
We will assess each trial according to the quality domains of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and any other potential threats to validity. In particular we will assess blinding separately for subjective (for example, length of hospital stay and well being) and objective (for example, insulin resistance) outcome measures as the latter are less likely to be affected by knowledge of the treatment allocation group.
We will consider a trial as having a low risk of bias if all domains are assessed as adequate. We will consider a trial as having a high risk of bias if one or more domain is assessed as inadequate or unclear. We will give reduced weight in the meta-analysis to studies with high risk of bias compared to studies at low (or lower) risk of bias. We will conduct sensitivity analyses to determine whether excluding studies at high risk of bias affects the results of the meta-analysis. We will report the 'Risk of bias' table as part of the table of 'Characteristics of included studies' and present a 'Risk of bias' summary figure which will detail all of the judgements made for all included studies in the review.
Measures of treatment effect
We will present categorical data as risk ratio and risk difference with 95% confidence intervals. We will calculate numbers needed to treat for benefit or harm, as appropriate. We will present continuous data as mean difference or standardised mean difference with 95% confidence intervals, as appropriate.
Unit of analysis issues
We will ensure that cluster-randomised trials are assessed for risk of bias and analysed as outlined in the Cochrane Handbook for Systematic Reviews of Interventions Chapter 16.3 (Handbook 2011).
Dealing with missing data
We will contact the nominated trial investigator for the included trials to obtain missing data necessary for meta-analysis (NH). We will calculate missing standard deviations from the standard errors or confidence intervals, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). Where standard deviations cannot be calculated, we will impute these using the mean of the reported standard deviations from the other trials. We will address the impact of missing data in the 'Discussion' section of the review.
Assessment of heterogeneity
We will assess the clinical heterogeneity of the included studies according to their clinical diversity (for example, different surgical procedures, different patient characteristics, different doses and timing of preoperative carbohydrate, etc.) and methodological diversity ('Risk of bias' assessment). We will address clinical heterogeneity using subgroup and sensitivity analyses. We will assess statistical heterogeneity using visual inspection of the forest plot, the I² statistic (Handbook 2011) and the Chi² test. We will consider an I² statistic of greater than 50% along with a P value of less than 0.10 in the Chi² test to be indicative of the need to further examine heterogeneity.
Assessment of reporting biases
We will assess publication bias and other small study effects in a qualitative manner using a funnel plot. We will test for funnel plot asymmetry using weighted linear regression of effect estimates on their standard error if more than 10 trials are included (Egger 1997).
If the degree of clinical heterogeneity is not excessive, we will generate a quantitative summary by meta-analysis. We will perform the meta-analysis using Review Manager software (RevMan 2012). We will perform both fixed-effect model and random-effects model meta-analyses and explore any differences between these two estimates.
Subgroup analysis and investigation of heterogeneity
We will perform subgroup analyses for subgroups of participants and interventions. We will compare subgroups using an interaction term if appropriate.
Subgroup analysis of the participants: according to type of surgery
- Anatomical site of surgery
- Type of reconstruction ('primary closure' versus 'free flap')
Subgroup analysis of the intervention
- Preoperative immunonutrition versus placebo drink
- Postoperative immunonutrition versus postoperative polymeric feed
We will perform sensitivity analyses to exclude trials at high risk of bias, such as quasi-randomised trials. We will compare random-effects and fixed-effect estimates of each outcome variable. If publication bias is suspected we will perform a 'trim and fill' sensitivity analysis of the primary outcomes. To assess trial influence we will perform sensitivity analyses by sequentially excluding each trial. We will use Stata (Stata 11, StataCorp) to perform sensitivity analyses not available in RevMan 5 (RevMan 2012).
We thank Jenny Bellorini, Managing Editor for the Cochrane Ear, Nose and Throat Disorders Group.
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Head and Neck Neoplasms] explode all trees and with qualifiers: [Surgery - SU]
#2 MeSH descriptor: [Otorhinolaryngologic Neoplasms] explode all trees and with qualifiers: [Surgery - SU]
#3 #1 or #2
#4 MeSH descriptor: [Otorhinolaryngologic Neoplasms] explode all trees
#5 MeSH descriptor: [Head and Neck Neoplasms] explode all trees
#6 head and neck
#7 (larynx or laryngeal or glottis or glottic or "oral cavity" or nasopharynx or nasopharyngeal or hypopharynx or hypopharyngeal or pharynx or pharyngeal or parapharyngeal or mouth)
#8 face or facial or oesophageal or esophageal or oesophagus or esophagus or thyroid or salivary or paranasal or "aero digestive" or aerodigestive or aero-digestive
#9 #6 or #7 or #8
#10 (cancer* or carcinoma* or neoplasm* or tumor* or tumour* or metastas*)
#11 MeSH descriptor: [Neoplasms] this term only
#12 #10 or #11
#13 #9 and #12
#14 #4 or #5 or #13
#15 MeSH descriptor: [Surgical Procedures, Operative] explode all trees
#16 (surg* or resect* or reconstruct*)
#17 (pharyngectomy or laryngopharyngectomy or laryngectomy or mandibulectomy or commando or esophagectomy or oesophagectomy) 327
#18 (neck and dissect*)
#19 MeSH descriptor: [Neck Dissection] explode all trees
#20 ((free or myocutaneous) and flap)
#21 #15 or #16 or #17 or #18 or #19 or #20
#22 #14 and #21
#23 #3 or #22
#24 MeSH descriptor: [Arginine] explode all trees
#25 immuno* or immune* or arginine* or glutamine* or omega-3 or omega3 or omega-6 or omega6 or "ω-3" or nucleotide* or nucleoside* or enhance* or enrich* or fibre* or fiber* or IMP1000 or IMP500
#26 MeSH descriptor: [Fatty Acids, Omega-3] explode all trees
#27 MeSH descriptor: [Fatty Acids, Omega-6] explode all trees
#28 MeSH descriptor: [Glutamine] explode all trees
#29 MeSH descriptor: [Nucleotides] this term only
#30 MeSH descriptor: [RNA] this term only
#31 MeSH descriptor: [Dietary Fiber] explode all trees
#32 isosource or jevity or vivonex or osmolite or nutrison or rna or Ribonucleic or impact
#33 Argininosuccinic* or Benzoylarginine* or Homoarginine* or Nitroarginine* or Tosylarginine* or Methylarginine* or NO2Arg or NOARG or L-NMMA or D-NMMA or TAME or Proglumide* or Xylamide* or Xilamide or Milid or PUFA* or "n-3 fatty acid*" or Docosahexaen* or Neuroprostane* or Icosapentaenoic* or Timnodonic or Linoleic* or Linolenic* or Octadecadienoic* or Linoleate* or Linoelaidic or "n-6 fatty acid*" or Eicosapentaenoic or EPA or O-3FA* or O-6FA*
#34 #24 or #25 or #26 or #27 or #28 #29 or #33 or #32 or #30
#35 enteral or polymeric* or Parenteral or diet* or feed* or food* or supplement* or nutri* or formul* or tpn or en or enteric or Nutraceutical* or tube* or pn or SEN or "Ensure Liquid*"
#36 MeSH descriptor: [Nutrition Therapy] this term only
#37 MeSH descriptor: [Nutritional Support] explode all trees
#38 MeSH descriptor: [Dietary Supplements] this term only
#39 MeSH descriptor: [Food, Formulated] this term only
#40 #35 or #36 or #37 or #38 or #39
#41 #34 and #40
#42 immunonutri* or immunoenhanc* or racol or RAC or IEEF or rakol or imn or ied or Sizofilan or SPG or Schizophyllum
#43 #41 or #42
#44 #23 and #43
Contributions of authors
- Conceiving the review: ST, SL and NH
- Designing the review: ST, SL and NH
- Co-ordinating the review: NH
- Undertaking manual searches: NH and MB
- Screening search results: ST, SL and NH
- Organising retrieval of papers: SL
- Screening retrieved papers against inclusion criteria: ST, SL and NH
- Appraising quality of papers: ST, SL and NH
- Abstracting data from papers: ST, SL and NH
- Writing to authors of papers for additional information: SL
- Obtaining and screening data on unpublished studies: SL
- Data management for the review: NH
- Entering data into Review Manager (RevMan 5.2): NH
- RevMan statistical data: NH and ST
- Other statistical analysis not using RevMan: NH and ST
- Double entry of data: (data entered by person one: NH; data entered by person two: ST)
- Interpretation of data: ST, SL and NH
- Writing the review: ST, SL and NH
- Providing guidance on the review: ST, SL and JB
- Securing funding for the review: N/A
- Performing previous work that was the foundation of the present study: ST and SL
- Guarantor for the review (one author): SL
- Person responsible for reading and checking review before submission: NH
Declarations of interest
ST and SL were involved in the design and conduct and publication of a study of postoperative feeding in colorectal surgery. Funding support for this study was provided by Nutricia Ltd. They have no pecuniary interest in the product used in any of the studies. NH has no known conflict of interest to declare.
Sources of support
- None, Not specified.
- None, Not specified.