Radiotherapy and corticosteroids for preventing and treating keloid scars

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of corticosteroids and radiotherapy in:

  • treating people with keloids;

  • preventing recurrence of keloid scarring in patients after surgical removal of keloids.

Background

Description of the condition

Keloid Scars

Keloid scars (keloids) are defined as benign outgrowths of fibrous (i.e. scar) tissue resulting from abnormal wound healing. They have the ability to spread outside the boundaries of the original lesion (Peacock 1970). As opposed to normal scars, keloids persist or continue to grow (Jackson 2001; Seifert 2009). Keloids are unique to humans and limited to the skin. Though benign in nature some authors have referred to keloids as tumours (Diao 2011).

Clinically, patients with keloids might present with symptoms of pruritus and pain in connection to cosmetic concern. Particular anatomical areas such as the chest, shoulder, upper back, neck and earlobes appear to be at high risk of keloid scarring. Histological examination of keloid scars reveals thicker collagen fibres and a prominent fascia-like fibrous band in the upper reticular dermis without contraction of the tissue (Ehrlich 1994).

Available epidemiological data indicate differences related to skin pigmentation, age and gender. The risk of developing a keloid scar is approximately 15 times higher in individuals with darker skin than with lighter skin (Alhady 1969). The incidence in an African population was 5.8%, with the highest rate of keloids occurring between the ages of 10 and 30 years, where it reached 42.3% (Oluwasanmi 1974). A case report described earlobe keloids in a 9 month old baby (Tirgan 2013). In 175 keloid patients seeking hospital treatment in Kuala Lumpur, 56% were Chinese, 23% Indian and 17% Malaysian. Of these patients, 80% were found to be younger than 30 years (Alhady 1969). In a World Health Organization (WHO) report on tuberculosis immunisation among children in the Philippines about 27% developed keloids when assessed 13 months after receiving the vaccine injection (Alhady 1969). There is a higher incidence of keloid disease in women which has been explained by their more frequent ear piercing (Oluwasanmi 1974) and hormonal factors (Dolores 2009).

The exact mechanism behind keloid scar development remains unclear. Skin trauma initiates the wound healing process (Oluwasanmi 1974) that eventually leads to keloid formation, although non-traumatic aetiologies have been reported (Dolores 2009; Jones 2006). Keloid heritability in an autosomal dominant pattern is supported by findings from twin and family studies (Clark 2009; Marneros 2001) as well as the association with certain syndromes, e.g. Rubinstein-Taybi and Goeminne (Seifert 2009). Several gene pathways have been implicated in keloid pathogenesis (Shih 2010). Transforming growth factor-beta and gene polymorphism analysis studies have failed to show significant associations with keloid disease whereas immunological reactions are likely to be involved in keloid aetiology (Seifert 2009).

The hallmark of keloids is excessive accumulation of extracellular matrix (ECM) components, notably collagen. The mechanisms responsible are poorly elucidated. Fibroblasts isolated from keloids show increased collagen synthesis but also decreased collagenolytic activity. The imbalance of the anabolic and catabolic processes may therefore result in the gradual accumulation of ECM in the lesion. Increased production of growth factors and their receptors may account for the increased number of fibroblasts and deposition of ECM. Decreased apoptosis of keloid fibroblasts is a common finding. Finally, fibrogenic factors produced by keloid keratinocytes and other cells (Gerd 2009) probably amplify the fibroproliferative processes further.

The time between skin trauma, including surgery, and onset of a keloid scar can be up to one year. It is not clear whether the duration of this lag-phase period depends on the type of injury (Oluwasanmi 1974).

Clearly cosmetic concern is an important aspect of this disease but pain, redness, pruritus, paraesthesia and functional impairment are all symptoms related to keloid (Alhady 1969; Brissett 2001). Severe impairment of quality of life in some patients with keloid scars has been demonstrated (Bock 2006) and a recent study identified a large discrepancy between the clinician's evaluation of a keloid scar and that of the patient, such that patients thought their scars were worse than the observers did. The discrepancy was not influenced by symptoms such as itching and pain (Nicholas 2012). Patients' concerns included the impact of their keloids on the quality of their life in terms of factors such as clothing, relationships and social activities.

Assessment

Scar assessment tools have been developed for grading scar appearance. The most widely used are the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scale (POSAS). VSS is a clinical assessment where the clinician grades pigmentation, pliability, vascularity and height on discrete scales. The total VSS score is calculated by adding these scores (Baryza 1995). The POSAS comprises both a clinical observer evaluation and a patient evaluation. The observer evaluation includes comparison of vascularity, pigmentation, thickness, relief, pliability, surface area in different subcategories with normal skin. The patient evaluation consists of questions regarding the scar about pain, itch, colour, stiffness, thickness and irregularity compared to normal skin. Scores are given on a 1-10 scale and overall score is the total of both the observer and patient part (Vercelli 2009). Quantitative assessments can also be performed e.g. pigmentation, erythema or elasticity measurements with non-invasive devices.

Therapies

There is no single effective therapeutic modality for the treatment of keloids. Keloids can be removed surgically but adjuvant therapy is necessary to prevent recurrence. Adjuvant therapies inhibit connective tissue deposition and first-line regimens include radiotherapy and intra- and postoperative steroid treatment. Other regimens encompass the chemotherapeutics bleomycin or 5-fluorouracil, the immunomodulator imiquimod, immune system mediators (interferons), the calcium antagonist verapamil, and mechanical prevention with pressure garments. Topical application of silicone in various forms, intralesional cryotherapy and photodynamic therapy have also been advocated (Nie 2010; Ogawa 2010).

There are limited cost analyses of treatment of keloids. Expenses associated with steroid injections are estimated to be USD 433 to 776 depending on the anatomical site (Anthony 2010). The costs associated with radiotherapy depend on the specific regimen, since newer modalities are more expensive. Radiotherapy generally results in a lower socio-economic burden compared with the other possible treatment modalities mentioned earlier because patients are generally treated as outpatients, equipment can in most cases be operated by nurses after initial settings have been made by the physician, each treatment takes only minutes and no following observation period is needed, in contrast to intralesional treatments which have a risk of an anaphylactic reaction.

Description of the intervention

Surgical treatment of keloids alone with no adjuvant therapy has a poor success rate, with a reported recurrence rate of around 80% after an average length of follow-up of 4.4 years (Cosman 1961); it is now considered obsolete. Recurrence rate after surgery with adjuvant radiotherapy probably depends on the radiation dose and treatment regimen, and a wide variation in success rates has been reported: between 56% (Yamawaki 2011) and 97.6% (Borok 1988) without any other adjuvant therapy.

Corticosteroid injections are used for treating keloids, and are mostly administered into the lesion itself (Jalali 2007). Topical steroid treatment is not a standard treatment (Perez 2010). Corticosteroid formulas include hydrocortisone acetate, methylprednisolone, dexamethasone and triamcinolone acetonide. They have been used for the treatment of pathological scars since the mid-1960s and also play a major role in preventing keloid recurrence as adjuvant therapy (Chen 2005). The most commonly used corticosteroid is triamcinolone. For treatment and prevention of recurrence after surgery, the dosage varies from 10 to 40 mg/mL and the drug is administered at intervals of four to six weeks for several months or until the scar is flattened in appearance (Chowdri 1999; Niessen 1999; Xiqiao 2009). In addition, topically applied corticosteroid can be used in both the prevention and the treatment of keloids (Darzi 2002; Manuskiatti 2002; Tang 1992).

Treatment with corticosteroids can be associated with local and systemic adverse effects, including hypopigmentation, dermal atrophy, telangiectasia, delayed wound healing and widening of the scar (Alster 2003; Asilian 2006; Manuskiatti 2002), and Cushing's syndrome (Finken 2010).

Surgery with removal of gross keloid substance followed by radiotherapy was first described in 1906 (De Bearman 1906). Currently radiotherapy following surgical removal of keloids is considered by some authors to be the first-line treatment (Recalcati 2011; Yamawaki 2011). However, the timing, duration, dose and therapeutic effect remain controversial. Radiotherapy is mostly initiated one to three days postoperatively, in weekly doses of five Gray (Gy) up to a total dose of 50 Gy (Recalcati 2011). There are different radiotherapy protocols that include external irradiation with superficial x-rays (photons) or β-rays (electron beams), or brachytherapy with β-rays (phosphorus-32, strontium-90 or yttrium-90) and γ-rays (cobalt-60 or iridium-192) (Ogawa 2009). Adverse effects reported are impaired wound healing (Jones 2006), hyperpigmentation, malignancy and recurrence (Brissett 2001).

Five cases of carcinogenesis associated with radiotherapy for keloids have been reported (Ogawa 2009). In a Canadian 10-year retrospective study in 96 keloid patients who had received radiotherapy none reported carcinogenesis (Speranza 2008). A survey among radiation oncologists showed that 78% found radiation therapy to be acceptable for the treatment of keloids (Leer 1998). Acute skin reactions due to radiation therapy occur during the first 7 to 10 days after treatment, presenting with erythema, pigmentation, epilation and desquamation. The degree of severity is dose-dependent. Subacute and late complications are scarring, permanent pigmentation, depigmentation, atrophy, telangiectasia, subcutaneous fibrosis, infection and (rarely) necrosis (Ogawa 2009; Speranza 2008). On a visual analogue scale from 1 to 10 (10 being absolute satisfaction) 60% of patients who received radiotherapy as an adjuvant treatment for keloids reported a score of more than 8 (Speranza 2008). Radiotherapy is therefore considered to be an appropriate adjuvant treatment for keloids.

How the intervention might work

Unwanted keloid tissue is removed through surgery and postoperative adjuvant therapy is needed to prevent recurrence.

Corticosteroids may reduce scar formation primarily by suppressing the inflammatory response and secondarily by diminishing collagen synthesis, inhibiting fibroblast growth and enhancing collagen loss (Fassler 1996; Perez 2001; Wu 2006).  A recent study demonstrated that corticosteroids alter the gene expression in scar formation, including the inhibition of TGF-β1 and TGF-β2 (which induce cells to proliferate and deposit excessive amounts of extracellular matrix) and collagens (COL4A1 and COL7A1) in keratinocytes (Sjojadinovic 2007).

The mechanism by which radiotherapy prevents keloids is poorly understood. Subcytotoxic doses of radiation immediately activate a DNA damage response that leads to fibroblast cell cycle arrest. The collagen synthesis is thus controlled, possibly by eradication of abnormally activated fibroblasts (Papadopoulou 2011; Sakamoto 2009).

Why it is important to do this review

Corticosteroid therapy or radiotherapy alone or in combination with surgery are first-line treatments for keloids. The scientific justification of these modalities is unclear. Furthermore, both modalities are associated with a range of side effects, which for some patients may be severe. Clinicians therefore still require clear evidence as to whether they are clinically effective and if so what are the most appropriate regimens.

Although keloid disease is benign it impacts heavily on psychological and physical quality of life and well-being (Nicholas 2012). It is particularly important for the clinician to balance the benefits of treatment with harm, and compare recurrence outcomes with alternative, less invasive adjuvant therapies. There is a substantial risk of developing keloid after trauma, especially burns (Patel 2012); surgery increases morbidity, loss of working days and occupational health needs for these patients.

Although surgery in combination with radiotherapy is considered a first-line treatment, the failure rates reported range between 2.4% and 44% (Borok 1988; Yamawaki 2011). The literature is sparse with respect to estimates of the costs involved in the treatment of keloids. The results from this review will shed light on the further research needed to estimate these costs.

The objective assessment of treatment efficacy and adverse effects in this review will help patients, clinicians and policy makers to improve the clinical decision-making process and implement best practice treatment protocols for keloid scar patients.

Objectives

To assess the effects of corticosteroids and radiotherapy in:

  • treating people with keloids;

  • preventing recurrence of keloid scarring in patients after surgical removal of keloids.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) or cluster-randomised trials. There will be no language restrictions (O'Connor 2011).

Types of participants

People of any age and pigmentation skin type as defined by Fitzpatrick 1988 with any type of keloid scar (e.g. after trauma, idiopathic, acne, surgery). Keloid is defined as abnormal scarring that extends beyond the original wound borders. A clinical diagnosis will be established by the clinician or investigator. Studies will not be limited to any particular clinical setting.

  • Treatment studies will consider people with established keloid scarring.

  • Prevention studies will consider people receiving adjunct treatment of the scar after the surgical removal of the keloid scar to prevent recurrence of keloid scarring.

Types of interventions

We will include:

  • treatment studies that compare corticosteroid and/or radiotherapy with other adjuvant therapies or none;

  • prevention studies that compare corticosteroid and/or radiotherapy with other adjuvant therapies or none after surgical removal.

Adjuvant therapies of interest in this review will include: corticosteroids, cryotherapy, verapamil, imiquimod, pressure garments, 5-fluorouracil (5-FU), bleomycin or photodynamic therapy. We will consider any adjuvant treatment, corticosteroid and radiotherapy regimen with regard to dose, frequency and duration.

Types of outcome measures

Primary outcomes

Primary outcomes in treatment studies:

  • change in keloid scar at the end of the study assessed by VSS, POSAS or other clinical or quantitative assessment tool (ruler or volume scans);

  • adverse effects including dyspigmentation, atrophy or ulcer (patients within allocated treatment group with adverse effects (yes or no)).

Primary outcomes in prevention studies:

  • keloid scar recurrence (yes or no which represents the presence or absence of keloid tissue at the original surgical scar removal site;

  • adverse effects including dyspigmentation, atrophy or ulcer (patients within allocated treatment group with adverse effects (yes or no)).

Secondary outcomes
  • Health-related quality of life measured by validated instruments, e.g. HRQoL (Guillemin 1993), SF-36 (Anderson 1993) or Questionnaire on Experience with Skin Complaints (Bock 2006). We anticipate that health-related quality of life outcomes will be presented as continuous data.

  • Economic burden, i.e. cost benefit analyses of radiotherapy versus steroid injection, bleomycin, imiquimod, 5-FU or other. We anticipate that cost estimates (continuous data) collected from individual studies will be presented in country-specific currencies and thus will need to be adjusted to a common currency and price year before these data are pooled.

We will report all outcomes in a 'Summary of findings' table.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases to identify reports of relevant randomised clinical trials:

  • the Cochrane Wounds Group Specialised Register;

  • the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) (latest issue);

  • Ovid MEDLINE (1946 to present);

  • Ovid EMBASE (1974 to present);

  • EBSCO CINAHL (1982 to present)

We will use the following two search strategies in the Cochrane Central Register of Controlled Trials (CENTRAL):

#1 MeSH descriptor: [Keloid] explode all trees
#2 MeSH descriptor: [Cicatrix, Hypertrophic] explode all trees
#3 (keloid* or hypertrophic or hypertropic or cicatrix):ti,ab,kw
#4 ("scar" or "scars" or scarred or scarring):ti,ab,kw
#5 #1 or #2 or #3 or #4
#6 MeSH descriptor: [Radiotherapy] explode all trees
#7 (radiotherap* or "radiation therapy"):ti,ab,kw
#8 MeSH descriptor: [Adrenal Cortex Hormones] explode all trees
#9 MeSH descriptor: [Steroids] explode all trees
#10 (glucocort* or corticosteroid* or steroid* or triamcinolone):ti,ab,kw
#11 #6 or #7 or #8 or #9 or #10
#12 #5 and #11

We will adapt this strategy to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. We will combine the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision) (Lefebvre 2011). We will combine the EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). We will combine the CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2011). We will not restrict studies with respect to language, date of publication or study setting.

We will search the following clinical trials registries:

Searching other resources

We will search reference lists of reviews, guidelines, retrieved studies and related articles for additional studies, as well as conference abstracts from the American Academy of Dermatology, European Academy of Dermatology and Venerology, American Society of Plastic Surgeons, European Tissue Repair Society and Wound Healing Society. We will contact corresponding authors to ask if they are aware of any unpublished studies.

Data collection and analysis

Two review authors will independently perform study eligibility assessment and extract data from study publications. We will identify and link together possible multiple reports of the same study. Specific criteria for comparing reports are author names, location and setting, specific details of the interventions, number of participants and baseline data, and date and duration of the study. When uncertainties cannot be clarified, it may be necessary to communicate with the authors of the reports.

We will design data collection forms carefully to target the objectives after consulting the Cochrane Wounds Group. We will trial the data collection form using two journal articles.

Selection of studies

Two review authors will independently inspect the results obtained through the search strategy as earlier specified. They will not be blinded to study information with regard to investigators, location etc. Where there is more than one report of the same study we will include all of them and extract as much information as possible. We will examine titles and abstracts and remove obviously irrelevant reports. If abstract results are not confirmed by subsequent publications we will try to contact the study authors.

We will examine full-text reports for compliance of studies with eligibility criteria. If appropriate, we will seek to contact the investigators, to clarify study eligibility or elucidate missing data. Finally, we will make decisions on study inclusion. If there are disagreements on whether a study should be included or not, a discussion will follow and if disagreement persists the third and fourth review author will examine the report and decide. A list of excluded studies will be included in the review with reasons for exclusion. We will complete a PRISMA flowchart (Liberati 2009).

Data extraction and management

Specific data items that will be extracted from included studies are:

  • source (publication source ID, study ID, country, year of publication, author ID and contact details);

  • methods (study design, duration, blinding, generation of sequence, allocation sequence concealment, concerns about bias);

  • participants (number, age, sex);

  • diagnostic criteria for keloid;

  • ethnicity or Fitzpatrick skin type;

  • intervention (total number of intervention groups, radiotherapy regimen (how long after surgery, dose, frequency, duration) and other adjuvant therapy regimen details);

  • other intervention details, e.g. integrity (compliance and follow-up);

  • outcomes (definition, measurement scale with upper and lower limit and whether a high or low score is a positive outcome), for each outcome of interest we will note the following: sample size, patients lost to follow-up, summary data, estimate of effect (risk ratio (RR), confidence interval (CI), P value).

  • and results (number of patients in each intervention group).

We will also record the following miscellaneous information: declaration of interest, funding source, key conclusions, what correspondence with authors was required and what the result of this might be, and the decision of the review authors (confirmation of eligibility or reason for exclusion).

We will maintain a copy of the original extracted data. If there are disagreements we will discuss these and resolve them. If consensus is not reached the third and fourth authors will be consulted. We will refer to the Cochrane Wounds Group editorial base where necessary (Higgins 2011a).

Assessment of risk of bias in included studies

Two review authors will independently assess each included study using The Cochrane Collaboration tool for assessing risk of bias (Higgins 2011b). This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues (e.g. extreme baseline imbalance) (see Appendix 1 for details of the criteria on which the judgement will be based). We will assess blinding and completeness of outcome data for each outcome separately. We will complete a 'Risk of bias' table for each eligible study. We will discuss any disagreement amongst all review authors to achieve consensus.

We will present our assessment of risk of bias, including data on the variation of duration of study follow-up and loss to follow-up, using a 'Risk of bias' summary figure, which presents all of the judgements in a cross-tabulation of study by entry. This display of internal validity indicates the weight the reader may give the results of each study.

Measures of treatment effect

The primary outcomes 'Keloid recurrence' (yes or no) and record of adverse effects (yes or no) are dichotomous data and will be presented as risk ratios (RRs) with 95% confidence intervals (CIs).

'Change in keloid scar at the end of the study' and the two secondary outcomes (health-related quality of life (HRQoL) and treatment costs) are continuous data and we will record mean difference (MD) and standard deviation (SD). We will adjust country-specific currencies to a common currency and price year before these data are pooled. When needed, we will try to obtain missing information or clarify statistical procedures by correspondence with the original study authors.

Unit of analysis issues

For each included study we will consider the level at which randomisation occurred, e.g. cluster-randomisation, patient randomisation or simultaneous treatment of multiple sites in each individual. We do not expect unit of analysis issues regarding cross-over trials.

We will carefully deal with unit of analysis issues regarding possible multiple body areas receiving the same or different interventions:

  1. If all keloids in different body parts of the same individual receive the same intervention we will include this person only once in the denominator.

  2. For trials where keloids in different body parts of the same individual receive different interventions, we will analyse measurements from each intervention and as such the number of keloid sites will be included in the denominator. This approach may give rise to a unit of analysis error due to large confidence intervals, with the consequence that such trials may be under-weighted in the meta-analysis. This may disguise clinically important heterogeneity. However, this type of analysis will most likely give rise to a more conservative outcome (effect towards the null hypothesis). We will undertake sensitivity analysis that excludes such trials to estimate the robustness of the summary effect measure.

Dealing with missing data

If data from the included studies are missing, we will contact the original investigators and request the data. We will make explicit any assumptions used to cope with missing data, for example, that the data are assumed missing at random, or that missing values are assumed to have a particular value such as a poor outcome. We will carry out sensitivity analyses to assess how sensitive results are to reasonable changes in the assumptions and we will address the potential impact of missing data on the findings of the review in the Discussion section (Higgins 2011a).

Assessment of heterogeneity

We will assess heterogeneity visually and statistically. We will present the study effect measures (e.g. RR) and 95% confidence intervals (CIs) graphically in a forest plot, and examine the overlap of CIs and the Chi2 tests.

We will also apply a statistical test to quantify inconsistency across studies (I2 statistic). The value of the I2 statistic (the proportion of variation between studies not due to chance) ranges from 0% to 100%. We will interpret findings according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions: 'Thresholds for the interpretation of I2, Chapter 9.5.2 (Deeks 2011). If substantial statistical heterogeneity is identified (I2 > 50%) strategies for addressing this will be as follows: we will check the data again and explore the heterogeneity, as one explanation could be groups of patients with different ages and skin pigmentation (Ioannidis 2008).

Assessment of reporting biases

We will create a funnel plot of intervention effect against the standard error of the intervention effect to assess whether there might be reporting bias. If more than 10 studies are included we will carry out a test for funnel plot asymmetry. If there is asymmetry or evidence of small study effects, we will consider possible explanations such as publication bias, selective outcome reporting, poor methodological design, inadequate analysis, true heterogeneity or chance (Sterne 2011).

Data synthesis

The primary aim is to perform meta-analysis to summarise the effectiveness of surgery plus radiotherapy compared with surgery plus other or no adjuvant intervention, e.g. surgery plus steroid injection.

We plan to use random-effects modelling for both primary (dichotomous) and secondary (continuous) outcomes on the basis that it assumes that treatment effects are not identical in all studies. A fixed-effect model assumes that the treatment effect is the same in each study and that differences in results are due only to chance. As stated above, we will quantify heterogeneity among studies using the I2 inconsistency statistic, which is a measure of inter-study variability. If inter-study variability is low (I2 < 30%) the fixed-effect and random-effects models will yield very similar results (Deeks 2011).

For the secondary outcome health-related quality of life (HRQoL) we anticipate that different validated quality of life instruments will have been used. We will also adjust cost estimates from individual studies to a common currency and price year. We will assess presentation of HRQoL and costs data in each study for normality. If data are normally distributed then we will take a standardised mean difference approach. In this instance, we will use standard deviations to standardise the mean differences to a single scale as well as the calculations of study weights.

If continuous data are presented as both log-transformed and untransformed data then such data cannot be mixed in a meta-analysis and we will present a narrative synthesis.

Subgroup analysis and investigation of heterogeneity

If heterogeneity exists then we will consider subgroup analysis for age (< 10, ≥ 10 to 29, ≥ 30 to 39, ≥ 40 years) and Fitzpatrick skin pigmentation type I-IV or V-VI (Fitzpatrick 1988) if individual studies indicate randomisation to treatment by these specific variables.

Sensitivity analysis

We will conduct sensitivity analysis to explore the impact of excluding trials at high risk of bias as identified by The Cochrane Collaboration tool for assessing risk of bias (Higgins 2011b) on risk estimates. Trials at overall high risk of bias will be those that have inadequate sequence generation, allocation concealment and blinding of outcome assessor. Since keloid risk of recurrence is highly dependent on follow-up time, we will also conduct sensitivity analysis to explore the impact on risk estimates of excluding trials with a short intervention follow-up time of less than 12 months.

Acknowledgements

The authors wish to thank the Cochrane Wounds Group (Rachel Richardson, Ian Smith, Nicky Cullum and Sally Bell-Syer) for kind and helpful guidance and assistance and the peer referees (Susan O'Meara, Gill Worthy, Evan Kontopantelis, David Margolis, Gisele de Olivera, Fiona Paton) and referees (Joyce Black, Mark Corbett, Audrey Demetriou and David Voegelicopy) and copy editor Jenny Bellorini.

Appendices

Appendix 1. Assessment of risk bias in included studies

1.  Was the allocation sequence randomly generated?

Low risk of bias

The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

High risk of bias

The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.

Unclear

Insufficient information about the sequence generation process to permit judgement of low or high risk of bias.

2.  Was the treatment allocation adequately concealed?

Low risk of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomisation); sequentially-numbered drug containers of identical appearance; sequentially-numbered, opaque, sealed envelopes.

High risk of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear

Insufficient information to permit judgement of low or high risk of bias. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

3.  Blinding - was knowledge of the allocated interventions adequately prevented during the study?

Low risk of bias

Any one of the following.

  • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.

  • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others unlikely to introduce bias.

High risk of bias

Any one of the following.

  • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.

  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, and the non-blinding of others likely to introduce bias.

Unclear

Any one of the following.

  • Insufficient information to permit judgement of low or high risk of bias.

  • The study did not address this outcome.

4. Were incomplete outcome data adequately addressed?

Low risk of bias

Any one of the following.

  • No missing outcome data.

  • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).

  • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size.

  • Missing data have been imputed using appropriate methods.

High risk of bias

Any one of the following.

  • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate.

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size.

  • ‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation.

  • Potentially inappropriate application of simple imputation.

Unclear

Any one of the following.

  • Insufficient reporting of attrition/exclusions to permit judgement of low or high risk of bias (e.g. number randomised not stated, no reasons for missing data provided).

  • The study did not address this outcome.

5. Are reports of the study free of suggestion of selective outcome reporting?

Low risk of bias

Any of the following.

  • The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.

  • The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon)

High risk of bias

Any one of the following.

  • Not all of the study’s pre-specified primary outcomes have been reported.

  • One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub scales) that were not pre-specified.

  • One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).

  • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis.

  • The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear

Insufficient information to permit judgement of low or high risk of bias. It is likely that the majority of studies will fall into this category.

6. Other sources of potential bias

Low risk of bias

The study appears to be free of other sources of bias.

High risk of bias

There is at least one important risk of bias. For example, the study:

  • had a potential source of bias related to the specific study design used; or

  • had extreme baseline imbalance; or

  • has been claimed to have been fraudulent; or

  • had some other problem.

Unclear

There may be a risk of bias, but there is either:

  • insufficient information to assess whether an important risk of bias exists; or

  • insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

Patricia L. Danielsen conceived the review question, developed and coordinated the protocol, completed the first draft, edited the protocol, performed part of the writing, made an intellectual contribution, approved the final version prior to submission, and is guarantor.
Ru Wang conceived the review question, edited the protocol, performed part of the writing, made an intellectual contribution, approved the final version prior to submission, and is guarantor.
Xiaoxi Zeng developed the protocol and performed part of writing or editing of the protocol, made an intellectual contribution to the protocol and advised on part of the protocol.
Yu Mao developed the protocol and performed part of writing or editing of the protocol, made an intellectual contribution to the protocol and advised on part of the protocol.
Magnus S. Ågren conceived the review question, developed the protocol, completed the first draft, performed part of the writing and editing, made an intellectual contribution, advised on the protocol, approved the final version prior to submission, and is guarantor.
Janine M. Duke edited the protocol, performed part of the writing, made an intellectual contribution, advised on the protocol, approved the final version prior to submission, and is guarantor.
Fiona Wood conceived the review question, developed the protocol, performed part of the writing and editing, made an intellectual contribution, advised on part of the protocol, approved the final version prior to submission, and is guarantor.
Ying Cen conceived the review question, developed the protocol, performed part of the writing and editing, made an intellectual contribution, advised on the protocol, approved the final version prior to submission, and is guarantor.

Declarations of interest

Magnus S. Ågren is a consultant for Mölnlycke Health Care AB, Sweden, Vivostat A/S, Denmark and Ethicon Endosurgery. The consultancy tasks are unrelated to the topic of the review and no conflict of interest is declared.
Fiona Wood: as a board member of Avita medical and cofounder of Clinical Cell Culture a conflict of interest regarding skin cell therapies is declared, this review does not relate to cultured cell and therefore is not related to the current commercial activities of the company.
Patricia L. Danielsen; Janine M. Duke; Ru Wang; Xiaoxi Zeng; Yu Mao and Ying Cen - none.

Contributions of editorial base:

Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content. Approved the final protocol prior to submission.
Sally Bell-Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited and copy edited the protocol.
Ruth Foxlee: designed the search strategy and edited the search methods section.
Rachel Richardson: advised on methodology, interpretation and content. Edited the protocol.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • NIHR/Department of Health (England), (Cochrane Wounds Group), UK.

Ancillary