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Behavioural and pharmaceutical interventions for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomised controlled trials

Objectives Solid organ transplant recipients are at increased risk of skin cancer, affecting more than 50% of recipients. We aimed to determine the effectiveness of interventions for behavioural change for sun protection or skin cancer prevention in solid organ transplant recipients. Design Systematic review. Data sources We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL from inception to November 2019. Eligibility criteria We included randomised controlled trials that evaluated the effect of behavioural or pharmaceutical interventions on behavioural change or skin cancer prevention in solid organ transplant recipients. Data extraction and synthesis Risks of bias and evidence certainty were assessed using Cochrane and the Grading of Recommendations Assessment Development and Evaluation framework. Results Twenty trials (n=2295 participants) were included. It is uncertain whether behavioural interventions improve sun protection behaviour (n=3, n=414, standardised mean difference (SMD) 0.89, 95% CI −0.84 to 2.62, I2=98%) and knowledge (n=4, n=489, SMD 0.50, 95% CI 0.12 to 0.87, I2= 76%) as the quality of evidence is very low. We are uncertain of the effects of mammalian target of rapamaycin inhibitors on the incidence of non-melanocytic skin cancer (n=5, n=1080, relative risk 0.46, 95% CI 0.28 to 0.75, I2 =72%) as the quality of evidence is very low. Conclusions Behavioural and pharmaceutical preventive interventions may improve sun protective behaviour and knowledge, and reduce the incidence of non-melanocytic skin cancer, but the overall quality of the evidence is very low and insufficient to guide decision-making and clinical practice. PROSPERO registration number CRD42017063962.

all authors contributed to the writing and review of the manuscript.

Disclosure
The authors declare no conflicts of interest.

ABSTRACT Objectives
Solid organ transplant recipients are at increased risk of skin cancer, affecting more than 50% of recipients. We aimed to determine the effectiveness of interventions for behavioral change for sun protection or skin cancer prevention in solid organ transplant recipients.

Methods
Electronic databases were searched from inception to January 2018. We included randomized controlled trials that evaluated the effect of behavioral or pharmaceutical interventions on behavioral change or skin cancer prevention in solid organ transplant recipients. Risks of bias and evidence certainty were assessed using Cochrane and the GRADE framework.

Results
Twenty trials (n=2,295 participants) were included. The overall risk of bias was low or unclear and the quality of evidence was very low for all outcomes. Compared with standard care, behavioral interventions appear to improve sun protection behavior (N=3, n= 414, SMD 0.89, 95% CI -0.84-2.62, I 2 =98%) and knowledge (N=4, n=489, SMD 0.50, 95% CI 0.12-0.87, I 2= 76%). Compared with calcineurin inhibitors, conversion to mammalian target of rapamaycin inhibitors may reduce the incidence of non-melanocytic skin cancer (N=5, n=1080, RR 0.46 95% CI 0.28-0.75, I 2 = 72%). Behavioral and pharmaceutical preventive interventions may improve sun protective behavior and knowledge, and reduce the incidence of non-melanocytic skin cancer, but the overall quality of the evidence is very low and insufficient to guide decision-making and clinical practice.

INTRODUCTION
Skin cancer, including melanoma and nonmelanoma skin cancer (NMSC), is the most frequently diagnosed malignancy among solid organ transplant recipients, affecting more than 50% of posttransplantation recipients. 1,2 The cumulative incidence of NMSC increases with time after transplantation, from 5-10% at 2 years to 40-80% at 20 years. [2][3][4] Squamous cell carcinomas (SCC) account for 95% of skin cancers diagnosed, with an incidence of 65 to 250 times greater than the age and gender-matched general population. [5][6][7] Once cancer develops, the excess risks of death from invasive and metastatic skin cancer, such as SCC and melanoma, are three times to nine times higher than the general population, with five-year overall survival of less than 30%. 6,[8][9][10][11] Sun exposure behaviors remain the most significant and modifiable risk factor in the prevention of skin cancers in the general population. 12 However, with the dramatic increase in skin cancers in solid organ transplant recipients, pharmaceuticals have also been used to reduce and delay the development of skin cancer. 12,13 Current recommendations for preventive strategies have often been extrapolated from guidelines in the general population, which may not be applicable to solid organ transplant recipients. 14 For example, frequent skin self-examination and annual to biannual total body skin examination are generally recommended for the general population. [14][15][16] Sun protective behaviors including use of sunscreen, protective clothing and limiting sun exposure during peak hours are potential measures for skin cancer prevention. 3,4,10 Further, alteration of maintenance immunosuppression such as conversion to mammalian target of rapamaycin inhibitors (mTORi) and secondary prevention using retinoid acitretin are recommended for management of skin cancers in high risk transplant recipients. 15 Page 8 of 49 For peer review only -http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  The aim of this study is determine the effectiveness of interventions that promote behavioral change and skin cancer prevention in solid organ transplant recipients.

METHODS
This systematic review followed a pre-specified protocol registered in PROSPERO (CRD4201706392) and is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. 17 The study was exempt from approval from an ethics' board. There was no patient or public involvement.

Inclusion criteria
All randomized controlled trials (RCTs) or quasi RCTs (allocated to trial arms by investigators) of interventions for skin cancer prevention (both melanoma and non-melanoma skin cancer) in solid organ transplant recipients were included. Behavioral interventions defined as any strategy used to promote sun protective behavior including passive (e.g. pamphlets), active (e.g. group workshops, counselling, dermatology clinic) and provision of sun protective equipment; and pharmaceutical interventions (switch to mTOR inhibitors, photodynamic therapy, immune response modifiers, nicotinamide and oral retinoids) and studies that reported skin cancer related outcomes as their primary outcomes were included. Studies that did not report these outcomes as primary end-points were excluded. Studies of interventions for the treatment of skin cancer were excluded.

Data extraction
Titles and abstracts were reviewed by two independent authors (LJJ & LL) and those that did not meet the inclusion criteria were excluded. Full text articles were reviewed by 3 independent reviewers (LJJ, VS, LL) and any disagreements were resolved by discussion. Data on study design, geographic location, sample size, type of transplant, measurement of interventions, interventions and comparators were extracted. We sought unclear or missing information from authors where possible.

Outcome measures
The pre-specified outcome measures were incidence of precancerous and cancerous lesions, sun protection behavior (including use of sunscreen, use of protective clothing including hats and sunglasses, shade and sun avoidance), knowledge and attitude, skin self-examination, sun exposure (including skin irritation, sunburn) and biologic measures (including measurement of melanin index and sun damage assessment).

Risk of bias and quality of evidence
The risk of bias was assessed independently by LJJ and VS using the Cochrane risk of bias tool. 18 The domains included in the assessment were: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, trial registration and industry involvement. Each criterion was assigned a judgment of high, low or unclear risk of bias. Intention to treat and lost to follow up were also assessed for each study. The quality of the evidence informing summary estimates for

Data synthesis and statistical analyses
Continuous outcomes were summarized as mean difference (MD) or standardized mean difference (SMD) and dichotomous outcomes as relative risk (RR). A MD/SMD greater than zero and/or a RR greater than 1 could be interpreted as favoring the intervention group relative to the control, unless specified elsewhere. Risk estimates were reported with 95% confidence intervals (CI), using random-effects meta-analysis. We considered P values <0.05 to be statistically significant. We quantified the heterogeneity using the I² statistic. An I 2 value of <25% was considered to represent low heterogeneity and >75% as high heterogeneity. When sufficient data were available, possible sources of heterogeneity were investigated using subgroup analysis based on pre-specified study characteristics including sample size, trial duration, setting and overall risk of bias. Funnel plots were planned to evaluate small study effects when at least ten studies were included in meta-analysis. All analyses were conducted using Review Manager version 5.3 software.

Study selection
The literature search identified 1099 articles, of which, 854 were excluded after abstract and title review. Full text assessment of 78 studies found 21 eligible articles for inclusion ( Figure 1).

Studies characteristics
We included 21 reports of 20 RCTs, including 2,295 participants ( Figure 1). The study characteristics are summarized in Table 1 and Table 2. The median number of participants was 44 (range 17 to 824) and the median follow-up duration was 10 months (range 1 day to 36 months). All studies included kidney transplant recipients, with some also including heart transplant recipients (n=1), liver, heart, pancreas, lung, heart/lung and other transplants (n=1), and lung and liver transplant recipients (n=2). In total, 15 of 21 (76%) studies provided sufficient data for the meta-analyses. Six studies did not meet final criteria for meta-analysis as they had the same sample of participants (n=1), 20 or did not provide data that was able to be meta-analyzed (n=5). 21-25

Risk of bias and quality of the evidence
Overall studies were at low or unclear risk of bias for many domains ( Figure 2; Figure S2).
Participants were blinded in 4 (20%), and outcome assessors were blinded in 10 (50%). Intention to treat analyses were used in 6 (30%) studies and 256 (11%) patients were lost to follow-up. A total of 3 (15%) studies had incomplete outcome data, and all studies were at low risk for selective reporting. Seven studies (35%) reported industry involvement in authorship, design, or data analysis, and of the 16 trials requiring trial registration, only 9 (56%) reported accordingly.
The overall quality of the evidence was very low for all outcomes (Table S1) due to limitations in study design, heterogeneity in the intervention and outcomes measures, the very small sample size of individual studies and the small number of studies for each specific outcome. Obtaining an overall summary estimate was difficult for many outcomes due to the variability in the analytical methods and reporting in individual studies. In particular, assessment of reporting of sun protection behavior and sun protection knowledge was not possible as outcomes were inconsistent and there was large diversity of interventions used (e.g. written education material versus a mobile app program). Furthermore, formal testing of publication bias was not performed due to insufficient data.

Interventions
The interventions in the included studies were grouped in three broad categories, behavioral (n=6), switch to mTOR inhibitors (n=6), and other pharmaceutical interventions (photodynamic therapy, immune response modifiers, oral retinoids and nicotinamide) (n=9). Studies of behavioral interventions used passive methods of delivery including written educational material (n=2), both written educational material and text messages (n=1), mobile app programs (n=2) and a video (n=1).
All six studies of immunosuppression compared mTORis (sirolimus) to calcineurin inhibitors (CNI) based therapies.
Four of the eight studies of other pharmaceutical interventions assessed the effect of photodynamic therapy using methyl aminolevinate creams compared to placebo (n=1), no treatment to contralateral area (n=2) or a topical immune response modifier cream (n=1). Three studies assessed oral retinoid using acitretin compared to placebo (n=1), lower dose (n=1) or a drug free period (n=1), one study assessed nicotinamide compared to placebo and a single study assessed the benefits of topical immune response modifier compared to placebo in kidney transplant recipients.

Sun protection behavior
Sun protection behavior, defined as hours spent outdoors per week, use of sunscreen, wearing protective clothing and seeking shade, was assessed in three trials [26][27][28] . Educational workbooks, 26 educational workbooks and text messages 27 and a mobile app program 28 were compared with standard care. Patients who received behavioral interventions reported improved sun protection  Figure 3). A single trial assessed a standardised and validated educational workbook and found an improvement in the proportion of participants engaging in skin self-examination after one month (75 participants, RR 4.14, 95% CI 2.22-7.72). 29 One trial assessed a mobile app program and reported a reduction in daily hours spent outdoors among the intervention group (170 participants, SMD -6.12, 95% CI -711 to -5.13). 28

Sun protection knowledge
The effectiveness of educational workbooks, text messages, mobile app programs and videos on sun protection knowledge was assessed in 6 studies 20,24,26-29 , four of which provided data for a meta-analysis. There was an improvement in knowledge scores (4 studies, 489 participants, SMD 0.50, 95% CI 0.12-0.87, I 2 76%) in the intervention group compared to standard care ( Figure 4). [26][27][28][29] One study compared an interactive visual representation of the educational program with standard information pamphlets and found that knowledge of sun protection improved among those who received the educational video. 24

Effect of pharmaceutical interventions on skin cancer prevention
The incidence and responses of pre-cancerous lesions were measured only in trials of pharmaceutical interventions (Table 4). These included the switch to mTOR inhibitors (n=1), 31 photodynamic therapy (n=2) 32,33 and immune response modifiers (n=1) 34 to current treatment, lower dose or no treatment. The incidence of non-melanocytic skin cancers (NMSC) was assessed in nine pharmaceutical studies. 1,31,[34][35][36][37][38][39][40] None included melanoma as an outcome. One trial of 14 participants compared an immune response modifier, 5% imiquimod cream with placebo and found a reduction in the incidence of skin dysplasia (RR 2.14, 95% CI 0.31-14.65), skin atypia (RR 3.00, 95% CI 0.47-19.35), and viral warts (RR 7.00, 95% CI 0.46-106.10). 34 One Danish study of 26 kidney transplant recipients compared photodynamic therapy with no treatment and reported a relative reduction by approximately 40% in the incidence of NMSC on the treated area (RR 0.59, 95% CI 0.34-21.03, p 0.06). 40 A lower incidence of SCC was also reported in one trial comparing two areas of skin using an immune response modifier and placebo (14 participants, RR 0.09, 95% CI 0.0.01-1.70). 34 Two trials comparing photodynamic therapy to an immune response modifier or photodynamic therapy to placebo in recipients with diagnosed keratoses reported a complete response rate of 60% compared to 24% in the control group (50 participants, RR 5.03, 95% CI 0.14-176.17, I 2 85%). 32,33 Further, one trial which was not included in the meta-analysis, reported a higher cumulative incidence of actinic keratosis lesions in untreated skin (63%) compared with skin treated by photodynamic therapy (28%). 23 Systemic interventions mTORis therapy reduced the incidence of NMSC compared to CNIs maintenance therapy (5 trials, 1082 participants, RR 0.46, 95% CI 0.28-0.75, I 2 72%) ( Figure 5). 1,31,35,37,39 However evidence was limited due to short follow-up periods, variability in dosing of mTORis and significant rates of loss to follow up. A single trial involving 21 patients reported a reduction in the overall incidence of SCC by 49% in the conversion arm, but reported a drop out rate of 77% and follow-up time of less than 2 years. 21

Subgroup analysis
Study size, trial duration, setting and risk of bias did not modify the effects of CNIs and mTORIs on skin cancer incidences ( Figure S3). Sources of heterogeneity for other treatment effects could not be explored due to insufficient data.

8-9
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

9
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

10-14
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

10-14
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

14-15
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

16
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.  all authors contributed to the writing and review of the manuscript.

Disclosure
The authors declare no conflicts of interest.

Data availability statement
No additional data available.

Objectives
Solid organ transplant recipients are at increased risk of skin cancer, affecting more than 50% of recipients. We aimed to determine the effectiveness of interventions for behavioral change for sun protection or skin cancer prevention in solid organ transplant recipients.

Data sources
Electronic databases were searched from inception to January 2018.

Eligibility Criteria
We included randomized controlled trials that evaluated the effect of behavioral or pharmaceutical interventions on behavioral change or skin cancer prevention in solid organ transplant recipients.

Data extraction and synthesis
Risks of bias and evidence certainty were assessed using Cochrane and the GRADE framework. ) and knowledge (N=4, n=489, SMD 0.50, 95% CI 0.12-0.87, I 2= 76%) as the quality of evidence is very low. We are uncertain of the effects of mammalian target of rapamaycin inhibitors on the incidence of non-melanocytic skin cancer (N=5, n=1080, RR 0.46 95% CI 0.28-0.75, I 2 = 72%) as the quality of evidence is very low.

Conclusions
Behavioral and pharmaceutical preventive interventions may improve sun protective behavior and knowledge, and reduce the incidence of non-melanocytic skin cancer, but the overall quality of the evidence is very low and insufficient to guide decision-making and clinical practice.

INTRODUCTION
Skin cancer, including melanoma and nonmelanoma skin cancer (NMSC), is the most frequently diagnosed malignancy among solid organ transplant recipients, affecting more than 50% of posttransplantation recipients. 1 2 The cumulative incidence of NMSC increases with time after transplantation, from 5-10% at 2 years to 40-80% at 20 years. [2][3][4] Compared to the general population, there is a higher rate of squamous cell carcinoma (SCC) to basal cell carcinoma (BCC), with an incidence of 65 to 250 times greater than the age and gender-matched general population. [5][6][7][8] Once cancer develops, management options are limited as immunotherapy may be unsuitable as it may lead to graft rejection. 9 10 Although registry data shows improvement in survival rates of transplant recipients as a result of improved transplantation techniques and management of immunosuppression, there is a greater burden of skin cancer and cancer related mortality. 11 The excess risk of death from invasive and metastatic skin cancer, such as SCC and melanoma, are three times to nine times higher than the general population, with five-year overall survival of less than 30%. 6 12-15 Sun exposure behaviors remain the most significant and modifiable risk factor in the prevention of skin cancers in the general population. 16 However, with the dramatic increase in skin cancers in solid organ transplant recipients, pharmaceuticals have also been used to reduce and delay the development of skin cancer. 16 17 Current recommendations for preventive strategies have often been extrapolated from guidelines in the general population, which may not be applicable to solid organ transplant recipients. 18 19 For example, frequent skin self-examination and annual to biannual total body skin examination are generally recommended for the general population. [18][19][20] Sun protective behaviors including use of sunscreen, protective clothing and limiting sun exposure during peak hours of high UV index days are potential measures for skin cancer prevention. 3 4 14  Further, alteration of maintenance immunosuppression such as conversion to mammalian target of rapamaycin inhibitors (mTORi) and secondary prevention using retinoid acitretin are recommended for management of skin cancers in high risk transplant recipients. 20 The aim of this study is determine the effectiveness of interventions that promote behavioral change and skin cancer prevention in solid organ transplant recipients.

METHODS
This systematic review followed a pre-specified protocol registered in PROSPERO (CRD42017063962) and is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. 21 The study was exempt from approval from an ethics' board.

Inclusion criteria
All randomized controlled trials (RCTs) or quasi RCTs (allocated to trial arms by investigators) of interventions for skin cancer prevention (both melanoma and non-melanoma skin cancer) in solid organ transplant recipients were included. Behavioral interventions defined as any strategy used to promote sun protective behavior including passive (e.g. pamphlets), active (e.g. group workshops, counselling, dermatology clinic) and provision of sun protective equipment; and pharmaceutical interventions (switch to mTOR inhibitors, photodynamic therapy, immune response modifiers, nicotinamide and oral retinoids) and studies that reported skin cancer related outcomes as their primary outcomes were included. Studies that did not report these outcomes as primary end-points were excluded. Studies of interventions for the treatment of skin cancer were excluded.

Search strategies
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL from inception to November 2019 without language restriction, using search strategies designed by a specialist information manager (see Medline search strategy in Figure S1).
Reference lists of included studies were also searched.

Data extraction
Titles and abstracts were reviewed by two independent authors (LJJ & LL) and those that did not meet the inclusion criteria were excluded. Full text articles were reviewed by 3 independent reviewers (LJJ, VS, LL) and any disagreements were resolved by discussion. Data on study design, geographic location, sample size, type of transplant, measurement of interventions, interventions and comparators were extracted. We sought unclear or missing information from authors where possible.

Outcome measures
The pre-specified outcome measures were incidence of precancerous and cancerous lesions, sun protection behavior (including use of sunscreen, use of protective clothing including hats and sunglasses, shade and sun avoidance), knowledge and attitude, skin self-examination, sun exposure (including skin irritation, sunburn) and biologic measures (including measurement of melanin index and sun damage assessment).

Risk of bias and quality of evidence
The risk of bias was assessed independently by LJJ and VS using the Cochrane risk of bias tool. 22 The domains included in the assessment were: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, trial registration and industry involvement. Each criterion was

Data synthesis and statistical analyses
Continuous outcomes were summarized as mean difference (MD) or standardized mean difference (SMD) and dichotomous outcomes as relative risk (RR). A MD/SMD greater than zero and/or a RR greater than 1 could be interpreted as favoring the intervention group relative to the control, unless specified elsewhere. Risk estimates were reported with 95% confidence intervals (CI), using random-effects meta-analysis. We considered P values <0.05 to be statistically significant. We quantified the heterogeneity using the I² statistic. An I 2 value of <25% was considered to represent low heterogeneity and >75% as high heterogeneity. When sufficient data were available, possible sources of heterogeneity were investigated using subgroup analysis based on pre-specified study characteristics including sample size, trial duration, setting and overall risk of bias. Funnel plots were planned to evaluate small study effects when at least ten studies were included in meta-analysis. All analyses were conducted using Review Manager version 5.3 software.

Patient and public involvement
There was no patient or public involvement.

Study selection
The literature search identified 1280 articles, of which, 1201 were excluded after abstract and title review. Full text assessment of 79 studies found 22 eligible articles for inclusion ( Figure 1).

Studies characteristics
We included 22 reports of 20 RCTs, including 2,295 participants ( Figure 1). The study characteristics are summarized in Table 1 and Table 2. The median number of participants was 44 (range 17 to 830) and the median follow-up duration was 10 months (range 1 day to 60 months).
All studies included kidney transplant recipients, with some also including heart transplant recipients (n=1), liver, heart, pancreas, lung, heart/lung and other transplants (n=1), and lung and liver transplant recipients (n=2). In total, 15 of 21 (76%) studies provided sufficient data for the meta-analyses. Six studies did not meet final criteria for meta-analysis as they had the same sample of participants (n=1), 24 or did not provide data that was able to be meta-analyzed (n=5). 25-29

Risk of bias and quality of the evidence
Overall studies were at low or unclear risk of bias for many domains ( Figure 2; Figure S2). Random sequence generation and allocation concealment were unclear in most studies (n=12, 60%).
Blinding of participants was not done in most studies (n=16, 80%) and blinding of outcome assessors was only reporting in half of the studies (n=10). Intention to treat analyses were used in 6 (30%) studies and 6 studies (30%) had a high loss to follow-up. A total of 3 (15%) studies had incomplete outcome data, and all studies were at low risk for selective reporting. Seven studies (35%) reported industry involvement in authorship, design, or data analysis, and of the 16 trials requiring trial registration, only 9 (56%) reported accordingly. The overall quality of the evidence was very low for all outcomes (Table S1) due to limitations in study design, heterogeneity in the intervention and outcomes measures, the very small sample size of individual studies and the small number of studies for each specific outcome. Obtaining an overall summary estimate was difficult for many outcomes due to the variability in the analytical methods and reporting in individual studies. In particular, assessment of reporting of sun protection behavior and sun protection knowledge was not possible as outcomes were inconsistent and there was large diversity of interventions used (e.g. written education material versus a mobile app program). Furthermore, formal testing of publication bias was not performed due to insufficient data.

Interventions
The interventions in the included studies were grouped in three broad categories, behavioral All six studies of immunosuppression compared mTORis (sirolimus) to calcineurin inhibitors (CNI) based therapies.
Four of the eight studies of other pharmaceutical interventions assessed the effect of photodynamic therapy using methyl aminolevinate creams compared to placebo (n=1), no treatment to contralateral area (n=2) or a topical immune response modifier cream (n=1). Three studies assessed oral retinoid using acitretin compared to placebo (n=1), lower dose (n=1) or a drug free period (n=1), one study assessed nicotinamide compared to placebo and a single study assessed the benefits of topical immune response modifier compared to placebo in kidney transplant recipients.

Sun protection behavior
Sun protection behavior, defined as hours spent outdoors per week, use of sunscreen, wearing protective clothing and seeking shade, was assessed in three trials 30

Sun protection knowledge
The effectiveness of educational workbooks, text messages, mobile app programs and videos on sun protection knowledge was assessed in 6 studies 24 28 30-33 , four of which provided data for a meta-analysis. There was an improvement in knowledge scores (4 studies, 489 participants, SMD 0.50, 95% CI 0.12-0.87, I 2 76%) in the intervention group compared to standard care ( Figure 4). 30-33 One study compared an interactive visual representation of the educational program with

Sun protection attitude
Three studies assessed sun protective attitude after receiving an educational workbook, text messages or a mobile app program over a period of 0.5 months to 1.5 months. 31-33 Compared to standard care, there was an overall improvement in scores of concern about developing cancer ( index (right forearm, SMD -0.42, 95% CI -0.66 to -0.18; cheek SMD -0.25, 95% CI -0.64 to -0.15) and reduced severity of sun damage (SMD -0.13, 95% CI -0.40 to 0.13) on sun exposed areas (measured using clinical images of chronic sun damage and scored 1-10).

Effect of pharmaceutical interventions on skin cancer prevention
The incidence and responses of pre-cancerous lesions were measured only in trials of pharmaceutical interventions (Table 4). These included the switch to mTOR inhibitors (n=1), 35 photodynamic therapy (n=2) 36 37 and immune response modifiers (n=1) 38 to current treatment or placebo. The incidence of non-melanocytic skin cancers (NMSC) was assessed in nine pharmaceutical studies. 1 35 38-44 None included melanoma as an outcome.

Topical/local interventions
One trial of 14 participants compared an immune response modifier, 5% imiquimod cream with placebo and found a reduction in the incidence of skin dysplasia (RR 2.14, 95% CI 0.

Subgroup analysis
Study size, trial duration, setting and risk of bias did not modify the effects of CNIs and mTORIs on skin cancer incidences ( Figure S3). Sources of heterogeneity for other treatment effects could not be explored due to insufficient data. Overall, the current evidence for interventions for skin cancer prevention in solid organ transplant recipients is of very low quality and is insufficient to guide decision-making and clinical practice. Although behavioral interventions appeared to improve sun protection attitude, knowledge and behavior, there were inconsistencies detected and none of these studies included skin cancer as an outcome. Due to limited number of studies, we were unable to compare specific behavioral interventions (e.g. mobile app vs. written education) to ascertain the most effective method of delivering sun protection education. While there may be some modest benefits in the reduction in cancer incidence (for NMSC) among solid organ transplant recipients who were converted to mTORIs compared to those on CNI maintenance, there was substantial heterogeneity across the studies that was unable to be explained by subgroup analyses. Heterogeneity may be attributed to the absence of long term follow up, large discontinuation rates owing to adverse events and variability in the doses of mTORIs. Pharmaceutical interventions (switch to mTOR inhibitors, photodynamic therapy, immune response modifiers) showed a reduction in precancerous lesions compared to standard care or a comparator group. However uncertainty exists in the treatment effects and there were too few studies, interventions were incomparable, follow-up times were variable and considerable loss to follow up for some studies to conclude that the benefits are sustainable.
Previous systematic reviews have evaluated the impact of behavioral interventions on skin cancer prevention in the general population, 45 and concluded that computer programs may increase sun protective behaviors, and 'appearance-focused' interventions may decrease sun tanning and UV exposure in adolescents and young women, respectively. Reviews conducted in other populations at high-risk including outdoor workers, 46 family history, personal history and phenotypic factors 47 have found similar improvement in sun protective behaviors, including use of sunscreen, as well as a decreased incidence of keratoses. A systematic review of the benefits and harms of oral  whilst most pharmacological intervention studies were conducted in Europe. There were also large discontinuation rates owing to adverse events in trials of mTORIs. Further, given the small number of studies included in the meta-analysis, we were unable to perform any detailed subgroup analyses to explore heterogeneity or assess for publication bias. While we were unable to show and assess publication bias using standard statistical tests, we would suggest the observed heterogeneity may also be attributed to potential publication and reporting biases. It is difficult to quantify the extent of such bias in this review, but one would expect research with 'positive' findings that indicate an intervention works, such as behavioral interventions improve sun protection, are more likely to be published more than one, in high impact journals and more likely to be cited. Finally, few trials included patient important outcomes associated with skin cancer and none included melanoma or mortality.
The use of pharmaceutical and immunosuppression therapy remains complex. Not only has mTORI therapy shown benefits in lowering the risk of skin cancer, early conversion to mTORI therapy from CNIs has also shown promising effects in reducing cancer rates. 49 50 On the contrary, overall mortality is higher and discontinuation following adverse events is more common in patients who receive mTORI therapy. 49 50 Several RCTs showed a higher rate of patients reporting adverse events or drug discontinuation with sirolimus, 1 41 43 demonstrating concern of its clinical usefulness. 49 Nicotinamide may also offer benefits to reducing skin cancer incidence by 20% and is relatively safe with minimal side effects. The protective effect of nicotinamide on skin cancer incidence in kidney transplant recipients is currently being explored in a phase 3 randomised controlled trial.
Although behavioral change is a simple strategy, long-term adherence remains challenging.
While behavioral counseling has been shown to increase sun protective behaviors in nontransplant populations, 45 there is no direct evidence to show that the behavioral change led to a reduction in morbidity and mortality. Previous studies have suggested that transplant recipients do not practice sun protective behaviors regularly, 51-53 were less likely to use sunscreen 54 and that patients have to perceive skin cancer as being an important risk to be motivated to change behavior. 55 56 However, studies on risk perception of transplant recipients remain conflicting.

8-9
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

9
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

10-14
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

10-14
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

14-15
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).   all authors contributed to the writing and review of the manuscript.

Disclosure
The authors declare no conflicts of interest.

Data availability statement
No additional data available.

ABSTRACT Objectives
Solid organ transplant recipients are at increased risk of skin cancer, affecting more than 50% of recipients. We aimed to determine the effectiveness of interventions for behavioral change for sun protection or skin cancer prevention in solid organ transplant recipients.

Data sources
Electronic databases were searched from inception to November 2019.

Eligibility Criteria
We included randomized controlled trials that evaluated the effect of behavioral or pharmaceutical interventions on behavioral change or skin cancer prevention in solid organ transplant recipients.

Data extraction and synthesis
Risks of bias and evidence certainty were assessed using Cochrane and the GRADE framework.

Conclusions
Behavioral and pharmaceutical preventive interventions may improve sun protective behavior and knowledge, and reduce the incidence of non-melanocytic skin cancer, but the overall quality of the evidence is very low and insufficient to guide decision-making and clinical practice.

INTRODUCTION
Skin cancer, including melanoma and nonmelanoma skin cancer (NMSC), is the most frequently diagnosed malignancy among solid organ transplant recipients, affecting more than 50% of posttransplantation recipients. 1 2 The cumulative incidence of NMSC increases with time after transplantation, from 5-10% at 2 years to 40-80% at 20 years. [2][3][4] Compared to the general population, there is a higher rate of squamous cell carcinoma (SCC) to basal cell carcinoma (BCC), with an incidence of 65 to 250 times greater than the age and gender-matched general population. [5][6][7][8] Once cancer develops, management options are limited as immunotherapy may be unsuitable as it may lead to graft rejection. 9 10 Although registry data shows improvement in survival rates of transplant recipients as a result of improved transplantation techniques and management of immunosuppression, there is a greater burden of skin cancer and cancer related mortality. 11 The excess risk of death from invasive and metastatic skin cancer, such as SCC and melanoma, are three times to nine times higher than the general population, with five-year overall survival of less than 30%. 6 12-15 Sun exposure behaviors remain the most significant and modifiable risk factor in the prevention of skin cancers in the general population. 16 However, with the dramatic increase in skin cancers in solid organ transplant recipients, pharmaceuticals have also been used to reduce and delay the development of skin cancer. 16 17 Current recommendations for preventive strategies have often been extrapolated from guidelines in the general population, which may not be applicable to solid organ transplant recipients. 18 19 For example, frequent skin self-examination and annual to biannual total body skin examination are generally recommended for the general population. [18][19][20] Sun protective behaviors including use of sunscreen, protective clothing and limiting sun exposure during peak hours of high UV index days are potential measures for skin cancer prevention. 3 4 14  Further, alteration of maintenance immunosuppression such as conversion to mammalian target of rapamaycin inhibitors (mTORi) and secondary prevention using retinoid acitretin are recommended for management of skin cancers in high risk transplant recipients. 20 The aim of this study is determine the effectiveness of interventions that promote behavioral change and skin cancer prevention in solid organ transplant recipients.

METHODS
This systematic review followed a pre-specified protocol registered in PROSPERO (CRD42017063962) and is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. 21 The study was exempt from approval from an ethics' board.

Inclusion criteria
All randomized controlled trials (RCTs) or quasi RCTs (allocated to trial arms by investigators) of interventions for skin cancer prevention (both melanoma and non-melanoma skin cancer) in solid organ transplant recipients were included. Behavioral interventions defined as any strategy used to promote sun protective behavior including passive (e.g. pamphlets), active (e.g. group workshops, counselling, dermatology clinic) and provision of sun protective equipment; and pharmaceutical interventions (switch to mTOR inhibitors, photodynamic therapy, immune response modifiers, nicotinamide and oral retinoids) and studies that reported skin cancer related outcomes as their primary outcomes were included. Studies that did not report these outcomes as primary end-points were excluded. Studies of interventions for the treatment of skin cancer were excluded.

Search strategies
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL from inception to November 2019 without language restriction, using search strategies designed by a specialist information manager (see Medline search strategy in Figure S1).
Reference lists of included studies were also searched.

Data extraction
Titles and abstracts were reviewed by two independent authors (LJJ & LL) and those that did not meet the inclusion criteria were excluded. Full text articles were reviewed by 3 independent reviewers (LJJ, VS, LL) and any disagreements were resolved by discussion. Data on study design, geographic location, sample size, type of transplant, measurement of interventions, interventions and comparators were extracted. We sought unclear or missing information from authors where possible.

Outcome measures
The pre-specified outcome measures were incidence of precancerous and cancerous lesions, sun protection behavior (including use of sunscreen, use of protective clothing including hats and sunglasses, shade and sun avoidance), knowledge and attitude, skin self-examination, sun exposure (including skin irritation, sunburn) and biologic measures (including measurement of melanin index and sun damage assessment).

Risk of bias and quality of evidence
The risk of bias was assessed independently by LJJ and VS using the Cochrane risk of bias tool. 22 The domains included in the assessment were: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, trial registration and industry involvement. Each criterion was

Data synthesis and statistical analyses
Continuous outcomes were summarized as mean difference (MD) or standardized mean difference (SMD) and dichotomous outcomes as relative risk (RR). A MD/SMD greater than zero and/or a RR greater than 1 could be interpreted as favoring the intervention group relative to the control, unless specified elsewhere. Risk estimates were reported with 95% confidence intervals (CI), using random-effects meta-analysis. We quantified the heterogeneity using the I² statistic. An I 2 value of <25% was considered to represent low heterogeneity and >75% as high heterogeneity.
When sufficient data were available, possible sources of heterogeneity were investigated using subgroup analysis based on pre-specified study characteristics including sample size, trial duration, setting and overall risk of bias. Funnel plots were planned to evaluate small study effects when at least ten studies were included in meta-analysis. All analyses were conducted using Review Manager version 5.3 software.

Patient and public involvement
There was no patient or public involvement.

Study selection
The literature search identified 1280 articles, of which, 1201 were excluded after abstract and title review. Full text assessment of 79 studies found 22 eligible articles for inclusion ( Figure 1).

Studies characteristics
We included 22 reports of 20 RCTs, including 2,295 participants ( Figure 1). The study characteristics are summarized in Table 1 and Table 2. The median number of participants was 44 (range 17 to 830) and the median follow-up duration was 10 months (range 1 day to 60 months).
All studies included kidney transplant recipients, with some also including heart transplant recipients (n=1), liver, heart, pancreas, lung, heart/lung and other transplants (n=1), and lung and liver transplant recipients (n=2). In total, 15 of 21 (76%) studies provided sufficient data for the meta-analyses. Six studies did not meet final criteria for meta-analysis as they had the same sample of participants (n=1), 24 or did not provide data that was able to be meta-analyzed (n=5). 25-29

Risk of bias and quality of the evidence
Overall studies had either high or unclear risk of bias for at least one domain (Figure 2; Figure S2).
Random sequence generation and allocation concealment were unclear in most studies (n=12, 60%). Blinding of participants was not done in most studies (n=16, 80%) and blinding of outcome assessors was only reporting in half of the studies (n=10). Intention to treat analyses were used in 6 (30%) studies and 6 studies (30%) had a high loss to follow-up. A total of 3 (15%) studies had incomplete outcome data, and all studies were at low risk for selective reporting. Seven studies (35%) reported industry involvement in authorship, design, or data analysis, and of the 16 trials requiring trial registration, only 9 (56%) reported accordingly.
The overall quality of the evidence was very low for all outcomes (Table S1) due to limitations in study design, heterogeneity in the intervention and outcomes measures, the very small sample size of individual studies and the small number of studies for each specific outcome. Obtaining an overall summary estimate was difficult for many outcomes due to the variability in the analytical methods and reporting in individual studies. In particular, assessment of reporting of sun protection behavior and sun protection knowledge was not possible as outcomes were inconsistent and there was large diversity of interventions used (e.g. written education material versus a mobile app program). Furthermore, formal testing of publication bias was not performed due to insufficient data.

Interventions
The interventions in the included studies were grouped in three broad categories, behavioral

Sun protection behavior
Sun protection behavior, defined as hours spent outdoors per week, use of sunscreen, wearing protective clothing and seeking shade, was assessed in three trials 30

Sun protection knowledge
The effectiveness of educational workbooks, text messages, mobile app programs and videos on sun protection knowledge was assessed in 6 studies 24 28 30-33 , four of which provided data for a meta-analysis. There was an improvement in knowledge scores (4 studies, 489 participants, SMD 0.50, 95% CI 0.12-0.87, I 2 76%) in the intervention group compared to standard care ( Figure 4). [30][31][32][33] One study compared an interactive visual representation of the educational program with standard information pamphlets and found that knowledge of sun protection improved among those who received the educational video. 28 reduced severity of sun damage (SMD -0.13, 95% CI -0.40 to 0.13) on sun exposed areas (measured using clinical images of chronic sun damage and scored 1-10).

Effect of pharmaceutical interventions on skin cancer prevention
The incidence and responses of pre-cancerous lesions were measured only in trials of pharmaceutical interventions (Table 4). These included the switch to mTOR inhibitors (n=1), 35 photodynamic therapy (n=2) 36 37 and immune response modifiers (n=1) 38 to current treatment or placebo. The incidence of non-melanocytic skin cancers (NMSC) was assessed in nine pharmaceutical studies. 1 35 38-44 None included melanoma as an outcome.

Topical/local interventions
One trial of 14 participants compared an immune response modifier, 5% imiquimod cream with placebo and found a reduction in the incidence of skin dysplasia (RR 2.14, 95% CI 0.

Subgroup analysis
Study size, trial duration, setting and risk of bias did not modify the effects of CNIs and mTORIs on skin cancer incidences ( Figure S3). Sources of heterogeneity for other treatment effects could not be explored due to insufficient data. Overall, the current evidence for interventions for skin cancer prevention in solid organ transplant recipients is of very low quality and is insufficient to guide decision-making and clinical practice.
Although behavioral interventions appeared to improve sun protection attitude, knowledge and behavior, there were inconsistencies detected and none of these studies included skin cancer as  whilst most pharmacological intervention studies were conducted in Europe. There were also large discontinuation rates owing to adverse events in trials of mTORIs. Further, given the small number of studies included in the meta-analysis, we were unable to perform any detailed subgroup analyses to explore heterogeneity or assess for publication bias. While we were unable to show and assess publication bias using standard statistical tests, we would suggest the observed heterogeneity may also be attributed to potential publication and reporting biases. It is difficult to quantify the extent of such bias in this review, but one would expect research with 'positive' findings that indicate an intervention works, such as behavioral interventions improve sun protection, are more likely to be published more than one, in high impact journals and more likely to be cited. Finally, few trials included patient important outcomes associated with skin cancer and none included melanoma or mortality.
The use of pharmaceutical and immunosuppression therapy remains complex. Not only has mTORI therapy shown benefits in lowering the risk of skin cancer, early conversion to mTORI therapy from CNIs has also shown promising effects in reducing cancer rates. 49 50 On the contrary, overall mortality is higher and discontinuation following adverse events is more common in patients who receive mTORI therapy. 49 50 Several RCTs showed a higher rate of patients reporting adverse events or drug discontinuation with sirolimus, 1 41 43 demonstrating concern of its clinical usefulness. 49 Nicotinamide may also offer benefits to reducing skin cancer incidence by 20% and is  55 56 However, studies on risk perception of transplant recipients remain conflicting.

6
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
6 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

6
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

6
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

8-9
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

9
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

10-14
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

10-14
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

14-15
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

16
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.  all authors contributed to the writing and review of the manuscript.

Disclosure
The authors declare no conflicts of interest.

Data availability statement
No additional data available.

ABSTRACT Objectives
Solid organ transplant recipients are at increased risk of skin cancer, affecting more than 50% of recipients. We aimed to determine the effectiveness of interventions for behavioral change for sun protection or skin cancer prevention in solid organ transplant recipients.

Data sources
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL from inception to November 2019.

Eligibility Criteria
We included randomized controlled trials that evaluated the effect of behavioral or pharmaceutical interventions on behavioral change or skin cancer prevention in solid organ transplant recipients.

Data extraction and synthesis
Risks of bias and evidence certainty were assessed using Cochrane and the GRADE framework.

Conclusions
Behavioral and pharmaceutical preventive interventions may improve sun protective behavior and knowledge, and reduce the incidence of non-melanocytic skin cancer, but the overall quality of the evidence is very low and insufficient to guide decision-making and clinical practice.

INTRODUCTION
Skin cancer, including melanoma and nonmelanoma skin cancer (NMSC), is the most frequently diagnosed malignancy among solid organ transplant recipients, affecting more than 50% of posttransplantation recipients. 1 2 The cumulative incidence of NMSC increases with time after transplantation, from 5-10% at 2 years to 40-80% at 20 years. [2][3][4] Compared to the general population, there is a higher rate of squamous cell carcinoma (SCC) to basal cell carcinoma (BCC), with an incidence of 65 to 250 times greater than the age and gender-matched general population. [5][6][7][8] Once cancer develops, management options are limited as immunotherapy may be unsuitable as it may lead to graft rejection. 9 10 Although registry data shows improvement in survival rates of transplant recipients as a result of improved transplantation techniques and management of immunosuppression, there is a greater burden of skin cancer and cancer related mortality. 11 The excess risk of death from invasive and metastatic skin cancer, such as SCC and melanoma, are three times to nine times higher than the general population, with five-year overall survival of less than 30%. 6 12-15 Sun exposure behaviors remain the most significant and modifiable risk factor in the prevention of skin cancers in the general population. 16 However, with the dramatic increase in skin cancers in solid organ transplant recipients, pharmaceuticals have also been used to reduce and delay the development of skin cancer. 16 17 Current recommendations for preventive strategies have often been extrapolated from guidelines in the general population, which may not be applicable to solid organ transplant recipients. 18 19 For example, frequent skin self-examination and annual to biannual total body skin examination are generally recommended for the general population. [18][19][20] Sun protective behaviors including use of sunscreen, protective clothing and limiting sun exposure during peak hours of high UV index days are potential measures for skin cancer prevention. 3 4 14  Further, alteration of maintenance immunosuppression such as conversion to mammalian target of rapamaycin inhibitors (mTORi) and secondary prevention using retinoid acitretin are recommended for management of skin cancers in high risk transplant recipients. 20 The aim of this study is determine the effectiveness of interventions that promote behavioral change and skin cancer prevention in solid organ transplant recipients.

METHODS
This systematic review followed a pre-specified protocol registered in PROSPERO (CRD42017063962) and is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. 21 The study was exempt from approval from an ethics' board.

Inclusion criteria
All randomized controlled trials (RCTs) or quasi RCTs (allocated to trial arms by investigators) of interventions for skin cancer prevention (both melanoma and non-melanoma skin cancer) in solid organ transplant recipients were included. Behavioral interventions defined as any strategy used to promote sun protective behavior including passive (e.g. pamphlets), active (e.g. group workshops, counselling, dermatology clinic) and provision of sun protective equipment; and pharmaceutical interventions (switch to mTOR inhibitors, photodynamic therapy, immune response modifiers, nicotinamide and oral retinoids) and studies that reported skin cancer related outcomes as their primary outcomes were included. Studies that did not report these outcomes as primary end-points were excluded. Studies of interventions for the treatment of skin cancer were excluded.

Search strategies
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL from inception to November 2019 without language restriction, using search strategies designed by a specialist information manager (see Medline search strategy in Figure S1).
Reference lists of included studies were also searched.

Data extraction
Titles and abstracts were reviewed by two independent authors (LJJ & LL) and those that did not meet the inclusion criteria were excluded. Full text articles were reviewed by 3 independent reviewers (LJJ, VS, LL) and any disagreements were resolved by discussion. Data on study design, geographic location, sample size, type of transplant, measurement of interventions, interventions and comparators were extracted. We sought unclear or missing information from authors where possible.

Outcome measures
The pre-specified outcome measures were incidence of precancerous and cancerous lesions, sun protection behavior (including use of sunscreen, use of protective clothing including hats and sunglasses, shade and sun avoidance), knowledge and attitude, skin self-examination, sun exposure (including skin irritation, sunburn) and biologic measures (including measurement of melanin index and sun damage assessment).

Risk of bias and quality of evidence
The risk of bias was assessed independently by LJJ and VS using the Cochrane risk of bias tool. 22 The domains included in the assessment were: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, trial registration and industry involvement. Each criterion was

Data synthesis and statistical analyses
Continuous outcomes were summarized as mean difference (MD) or standardized mean difference (SMD) and dichotomous outcomes as relative risk (RR). A MD/SMD greater than zero and/or a RR greater than 1 could be interpreted as favoring the intervention group relative to the control, unless specified elsewhere. Risk estimates were reported with 95% confidence intervals (CI), using random-effects meta-analysis. We quantified the heterogeneity using the I² statistic. An I 2 value of <25% was considered to represent low heterogeneity and >75% as high heterogeneity.
When sufficient data were available, possible sources of heterogeneity were investigated using subgroup analysis based on pre-specified study characteristics including sample size, trial duration, setting and overall risk of bias. Funnel plots were planned to evaluate small study effects when at least ten studies were included in meta-analysis. All analyses were conducted using Review Manager version 5.3 software.

Patient and public involvement
There was no patient or public involvement.

Study selection
The literature search identified 1280 articles, of which, 1201 were excluded after abstract and title review. Full text assessment of 79 studies found 22 eligible articles for inclusion ( Figure 1).

Studies characteristics
We included 22 reports of 20 RCTs, including 2,295 participants ( Figure 1). The study characteristics are summarized in Table 1 and Table 2. The median number of participants was 44 (range 17 to 830) and the median follow-up duration was 10 months (range 1 day to 60 months).
All studies included kidney transplant recipients, with some also including heart transplant recipients (n=1), liver, heart, pancreas, lung, heart/lung and other transplants (n=1), and lung and liver transplant recipients (n=2). In total, 15 of 21 (76%) studies provided sufficient data for the meta-analyses. Six studies did not meet final criteria for meta-analysis as they had the same sample of participants (n=1), 24 or did not provide data that was able to be meta-analyzed (n=5). 25-29

Risk of bias and quality of the evidence
Overall studies had either high or unclear risk of bias for at least one domain (Figure 2; Figure S2).
Random sequence generation and allocation concealment were unclear in most studies (n=12, 60%). Blinding of participants was not done in most studies (n=16, 80%) and blinding of outcome assessors was only reporting in half of the studies (n=10). Intention to treat analyses were used in 6 (30%) studies and 6 studies (30%) had a high loss to follow-up. A total of 3 (15%) studies had incomplete outcome data, and all studies were at low risk for selective reporting. Seven studies (35%) reported industry involvement in authorship, design, or data analysis, and of the 16 trials requiring trial registration, only 9 (56%) reported accordingly.
The overall quality of the evidence was very low for all outcomes (Table S1) due to limitations in study design, heterogeneity in the intervention and outcomes measures, the very small sample size of individual studies and the small number of studies for each specific outcome. Obtaining an overall summary estimate was difficult for many outcomes due to the variability in the analytical methods and reporting in individual studies. In particular, assessment of reporting of sun protection behavior and sun protection knowledge was not possible as outcomes were inconsistent and there was large diversity of interventions used (e.g. written education material versus a mobile app program). Furthermore, formal testing of publication bias was not performed due to insufficient data.

Interventions
The interventions in the included studies were grouped in three broad categories, behavioral

Subgroup analysis
Study size, trial duration, setting and risk of bias did not modify the effects of CNIs and mTORIs on skin cancer incidences ( Figure S3). Sources of heterogeneity for other treatment effects could not be explored due to insufficient data. Overall, the current evidence for interventions for skin cancer prevention in solid organ transplant recipients is of very low quality and is insufficient to guide decision-making and clinical practice.

DISCUSSION
Although behavioral interventions appeared to improve sun protection attitude, knowledge and behavior, there were inconsistencies detected and none of these studies included skin cancer as  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  whilst most pharmacological intervention studies were conducted in Europe. There were also large discontinuation rates owing to adverse events in trials of mTORIs. Further, given the small number of studies included in the meta-analysis, we were unable to perform any detailed subgroup analyses to explore heterogeneity or assess for publication bias. While we were unable to show and assess publication bias using standard statistical tests, we would suggest the observed heterogeneity may also be attributed to potential publication and reporting biases. It is difficult to quantify the extent of such bias in this review, but one would expect research with 'positive' findings that indicate an intervention works, such as behavioral interventions improve sun protection, are more likely to be published more than one, in high impact journals and more likely to be cited. Finally, few trials included patient important outcomes associated with skin cancer and none included melanoma or mortality.

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

14-15
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

16
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.