Brief overview
Surveillance strategies vary in a number of ways: by duration and frequency of contact with patients, and in terms of which practitioner sees patients, and in what type of diagnostic and prognostic tools are used. In a systematic review of surveillance strategies, all the countries that provided data on surveillance had programmes that followed patients for 5 years after treatment and recommended between one and six visits per year, in addition to recommended self-examination.25 Self-examination is important because many (if not most) melanoma recurrences are detected by patients themselves.76 As outlined in Chapter 2, not all countries use diagnostic imaging in surveillance visits, but many use sonography; radiography of the regional nodal basin, chest or abdomen; clinical photography; or positron emission tomography (PET), CT or magnetic resonance imaging (MRI). Some also assess a patient’s blood count and liver function.
The NICE guideline for melanoma77 recommends that, after stage IA, patients are seen by a clinician between two and four times in the first year after completion of treatment, and then discharged. After stages IB to IIB melanoma, or stage IIC melanoma with a negative SLNB, the guideline recommends that patients are followed up every 3 months for 3 years and then every 6 months for the next 2 years, after which they can be discharged. No imaging or blood tests are recommended during follow-up for either of these groups.
As described in Chapter 2, there is little consensus about the most effective and cost-effective way to follow up patients who have been treated for melanoma. Furthermore, the evidence base for the different strategies adopted is unclear. Previous studies suggest that existing guidance, which includes variation in frequency and duration of patient contact, as well as in recommended diagnostic and prognostic tools, is based on anecdotal evidence or retrospective assessment of historical cohorts.25,76
To clarify what evidence there is to support any surveillance for stage I melanoma, a high-quality systematic review is needed. This systematic review would be used to gather and synthesise the most robust evidence about all elements of surveillance strategies for melanoma.
Methods
This review adheres to the guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to ensure transparency of the process.78 A protocol for the whole project of which this review is part is published on PROSPERO (CRD42018086784).79
Search strategy
The search strategy was designed by an experienced information specialist in collaboration with the project team. The search was designed in MEDLINE [via Ovid® (Wolters Kluwer, Alphen aan den Rijn, the Netherlands)] according to the following main concepts: [melanoma] AND [surveillance OR screening]. Database-specific thesaurus headings were used, together with title and abstract keywords. The strategy was translated to other databases (Box 2), altering thesaurus headings and search syntax as appropriate. The databases listed in Box 2 were searched during the first week of May 2018 and the search was updated on 2 July 2019.
Databases searched for surveillance review
The search was then limited to studies published from 2011 onwards, the search date of a previously published systematic review of surveillance strategies for melanoma.25 There were no restrictions according to language or publication status. The search strategy used in MEDLINE can be found in Appendix 1.
We did not update the systematic review authored by Cromwell et al.;25 instead, we used it to identify publications prior to 2011. To reduce the screening burden of systematically searching from database inception, we screened all studies included in this review.25 Full references of the review were also screened, in addition to the results of the systematic search limited to studies published from 2011 onwards.
A grey literature search plan was developed to complement this search by exploring (1) grey literature databases, (2) targeted websites and (3) reference leads from (1) and (2), with a focused attempt to locate international and national guidelines. By checking the references of international guidelines and the studies cited in a review by Cromwell et al.25 extended out search to before the 2011 limit described above. The sources described in Box 3 were searched between 20 July 2018 and 10 September 2018.
Sources searched for grey literature in surveillance review
Titles and abstracts of search results were imported into EndNote [Clarivate Analytics (formerly Thomson Reuters), Philadelphia, PA, USA] and deduplicated.
Inclusion and exclusion criteria
We based inclusion and exclusion criteria on the population, intervention, comparator, outcomes, timing and setting (PICOTS) formula, as outlined in the following sections.80
Population
Adults aged ≥ 18 years treated for AJCC (eighth edition) stage I cutaneous melanoma [stage IA (≤ 0.8 mm thick without ulceration) or stage IB (< 0.8 mm thick, or < 1 mm thick and ulcerated skin)].19
Or:
Adults aged ≥ 18 years treated for AJCC (seventh edition) stage I cutaneous melanoma [stage IA (T1a ≤ 1 mm thick) or stage IB (T1b with ulceration or mitoses ≤ 1 mm thick, or T2a 1.01 to 2.00 mm thick and no ulceration)].20
Non-randomised studies reporting patients with varying stages of cutaneous melanoma were included if ≥ 80% cases were at stage I, as we expected data to be sparse and did not want to omit potentially relevant evidence. Studies that did not specify a patient population were initially included pending confirmation from study authors. However, none of these met the inclusion criteria; therefore all were excluded. Studies reporting the Breslow depth, for patients with tumours of ≤ 2 mm, were included if there were no data on AJCC stage. Studies that included only patients with stage II–IV melanoma were excluded.
Intervention
We included studies that had any surveillance or follow-up strategies aiming to identify further primary melanoma, local recurrence or in-transit, regional or distant metastases. These were not limited by setting or by the type of clinician undertaking the follow-up. They could include clinical evaluation, patient education, skin self-examination (SSE) or radiological examination at any frequency. We excluded studies that focused on treatment of melanoma rather than surveillance.
Comparator
Studies with any comparator that allowed for the assessment of relative clinical effectiveness were eligible for inclusion (i.e. no surveillance or an alternative strategy).
Outcomes
The following were the outcomes of interest: overall survival, progression-free or recurrence-free survival, melanoma-specific survival, detection of recurrence as a new primary tumour, in-transit metastases and locoregional metastases. This could be presented as dichotomous or time-to-event data, such as percentages, hazard ratios (HRs), risk ratios (RRs) or Kaplan–Meier plots. No restrictions were placed on how outcomes were determined or confirmed (e.g. through biopsy, histology or imaging); all study-defined outcomes were allowed.
Timing
The timing for onset of surveillance strategies was restricted to patients who were post resection of any primary cutaneous melanoma tumours. The duration of surveillance (follow-up) was determined by individual studies and interpreted accordingly.
Setting
All studies were eligible for inclusion, regardless of whether the study was conducted in primary, secondary or tertiary care. No restrictions were applied to countries of origin conducting the primary research, although the relevance to current or future UK practice was assessed.
Study designs
We included RCTs and non-randomised comparative studies, for example quasi-experimental and comparative retrospective or prospective observational studies. We also looked at guidelines that recommended strategies for surveillance of stage I melanoma so that we could search their references for eligible studies. We excluded potentially underpowered non-RCT studies (arbitrarily defined as having < 100 patients) because they are at risk of selective reporting bias and publication bias, and they lead to small-study effects with imprecision.
To minimise selection bias in non-randomised study designs, we included studies that used statistical adjustment for baseline case mix using multivariate analyses, provided that the study had at least 80% stage I patients. We expected to see variables such as age, sex, ethnicity, tumour stage and grade, histology or performance status as adjustment variables; we excluded comparative observational studies if they did not adjust for at least two of these variables.
Data collection
Selection of studies
Selection of studies that met the inclusion criteria was conducted in two stages. In the first instance, studies were exported from the EndNote library and into Rayyan (Qatar Computing Research Institute, Doha, Qatar), a web-based tool designed to aid screening and selection of studies for systematic reviews.81 For consistency and accuracy, two sets of two reviewers initially piloted the screening process. This was done by assessing 10% of the titles and abstracts, along with some full text studies, against the prespecified inclusion and exclusion criteria. Disagreements at this stage were resolved by either discussion between the reviewers or arbitration with another member of the study team. In the second stage, studies that appeared to meet the inclusion and exclusion criteria were imported into EndNote and full-text papers obtained. When full texts were not readily available, we accessed articles via interlibrary loans. Two reviewers independently evaluated these articles and made their selection in accordance with the eligibility criteria.
Data extraction
A data extraction form was created in Microsoft Word (Microsoft Corporation, Redmond, WA, USA) in accordance with Cochrane guidelines82 and piloted on one study prior to use. After necessary adjustments, one reviewer undertook the data extraction of the included articles. The completed extraction form was checked for accuracy, completeness and consistency by a second reviewer. When stage I data were grouped with other stages of disease in an included study, we contacted the study authors, which led to us obtaining the relevant data for patients with stage I disease. We also contacted authors to obtain missing data or to clarify uncertainties. The following domains were extracted: country of origin, patient characteristics, study objectives, study design, tumour characteristics, follow-up regimens, analysis methods, risk of bias, outcomes and conclusions. An example of the data extraction form can be found in Report Supplementary Material 1.
When possible, all data extracted were those relevant to an intention-to-treat analysis, in which participants were analysed in the groups to which they were assigned. The time points at which outcomes were collected and reported were recorded.
Guidelines that recommended strategies for surveillance of stage I melanoma did not form part of the systematic review. However, to provide context, they were summarised and their conclusions are presented in Summary of review of different surveillance strategies.
Risk-of-bias assessment in included studies
We used the Cochrane Collaboration’s ‘Risk-of-bias’ tool, RoB 2.0, which uses signalling questions to assess risk-of-bias judgements.83 The tool examines five domains graded as being at a low risk-of-bias, of some concern or at a high risk of bias, from which an overall risk-of-bias judgement can be made. The domains considered are biases resulting from the randomisation process, deviations from the intended intervention, missing outcome data, measurement of outcomes, and selection of reported results.
Measures of effect
We planned to extract the following reported measures of effects of surveillance:
dichotomous or binary data, odds ratios (ORs) or RRs or percentages
time-to-event data, HRs or Kaplan–Meier plots.
Confidence intervals for all estimates missing data
We set out to report the number (per cent) of missing data for all variables/outcomes. We did not impute missing outcome data for any of our specified outcomes.
Data analysis
We summarised the characteristics of the surveillance strategies from included studies and guidelines in a table and provided a narrative summary of these.
We planned to conduct random-effects meta-analyses to pool data for each outcome in the review. In the absence of sufficiently robust or similar studies for a meta-analysis, we carried out a summary of studies, rather than a more formal narrative synthesis, owing to a lack of evidence.
Quality of the evidence using the GRADE approach
The GRADEpro tool was used to assess the overall certainty in the body of evidence for key outcomes.84 The GRADE approach uses the risk of bias of individual studies, along with characteristics such as the imprecision and inconsistency of their results, to produce an overall estimate in terms of whether there is high, moderate, low or very low confidence that the systematic review estimates the true effect. These data are presented as a summary of findings table (see ).
Summary of findings: systematic review to identify different surveillance and follow-up strategies for stage I melanoma patients following surgical excision
Results
Number of studies identified
The searches retrieved 10,723 citations in total; 10,592 were retrieved from the electronic databases, 104 from the published systematic review25 and 27 from the grey literature and guidelines search (). After deduplication, 6205 references remained. Following a title and abstract sift by one reviewer and two clinicians, 6134 references were excluded, resulting in 33 citations of articles and conference abstracts for full-text assessment.
The PRISMA flow diagram for the review of surveillance strategies’ clinical effectiveness.
Following this, we excluded 31 articles. The reasons for excluding the full-text papers were as follows: < 80% of participants at stage I or wrong stage (58%), and studies identified as prognostic studies (26%) diagnostic studies (10%) or prevention studies (6%). In addition, all included studies from the Cromwell et al.25 systematic review were excluded because they were not surveillance strategies among individuals post resection of a stage I melanoma, and most included studies had a non-comparative design.25 A list of excluded full-text articles retrieved from the literature search, with reasons for exclusion, is provided in Appendix 2.
Authors of relevant studies presenting aggregated data were contacted to provide data stratified by stage. Correspondence was received from Robinson et al.85 and Damude et al.;23 however, only Robinson et al.85 provided data that fulfilled our inclusion criteria.
Characteristics of included studies
One RCT met our inclusion criteria85,86 after provision of further data by the authors. Robinson et al.85 assessed the frequency of SSE by patient–partner dyads. The study was conducted in the USA.85 The study included a total of 494 participants with a mean age of 55 years [standard deviation (SD) ±10 years, range 18 to > 70 years). Descriptive information of the study is presented in .
Description of included studies for the review of guideline surveillance strategies
Patients with stage 0–IIB melanoma participated in the trial from June 2011 to April 2015. This was a continuation of the trial initially reported by Turrisi et al.87 Patients in the intervention arm received a structured skills training intervention, whereas patients in the control arm received customary care.
A total of 494 patients and their partners were randomised to one of four groups. Three of the dyad groups received a structured skills training intervention in SSE, either in person, from a written workbook or via a tablet. The fourth group served as control and received treatment as usual87 and customary education.85 Patients were seen by a dermatologist every 4 months. The primary outcome was frequency of SSE by patient–partner dyads, and the follow-up period and end point of the trial was 24 months. The secondary outcome was detection of a new or recurrent melanoma by the dyad or physician.
Patients at stages 0–IIB receiving the intervention had significantly increased SSEs with their partners at 4 months, compared with controls [mean difference 1.57, 95% confidence interval (CI) 1.29 to 1.85]. Mean differences at 12 and 24 months were lower (mean difference 0.72, 95% CI 0.39 to 1.06, and mean difference 0.94, 95% CI 0.58 to 1.30, respectively). Overall, data reported for stages 0–IIB showed that the intervention was successful in increasing SSE by patient–partner dyads, compared with controls at 24 months (mean difference 0.94, 95% CI 0.58 to 1.30; p < 0.001). We contacted the authors for data by disease stage, which were provided by them for our analyses.
The individuals undertaking surevillance (through SSE) of the outcome of interest to our review (detection of a new primary tumour, recurrent melanoma or metastases) were both the dyad and physician, with the site of surveillance being either the home or the care setting of the dermatologist (predominantly a secondary care setting). The interval timing of the review appointments with the dermatologist were 4 months; however, for surveillance by the dyad, the interval timing was dependent on their own timeline of use of SSE. The duration of follow-up for the surveillance in the trial, and thus by dermatologists, was 2 years. However, the SSE by the dyads was intended to last for life. There was no routine imaging involved in the surveillance strategy; rather, the strategy was based on a structured skills training intervention on how to self-identify plausible new or recurrent melanoma. Given that the study reported that SSE increased, it has been assumed that this surveillance stratgey is well accepted by melanoma patients. There is no large burden on health-care providers due to surveillance by SSE.
Risk-of-bias assessment of included studies
It was judged that there were ‘some concerns’ regarding the risk of bias in the study by Robinson et al.85 Two allied papers were used to identify data pertinent to the risk-of-bias assessment.86,87 The results are discussed in the following sections, and the judgements made using the Cochrane risk-of-bias tool, RoB 2.0,83 are shown in .
Risk of bias for the systematic review of surveillance strategies
Bias from randomisation process
Reviewers considered the randomisation process as giving rise to some concerns.85 There were baseline imbalances in the number of participants assigned to each of the intervention arms. The first 150 pairs were randomised to one of the three groups (workbook, in person or control), and the remaining 344 pairs were randomised to one of four groups (workbook, in person, tablet or control).85
Bias from deviations of intended interventions
The study was judged to be at a low risk of bias. No deviations from the intended interventions were reported. However, an additional intervention (using a tablet computer) was added while recruitment was ongoing.
Bias due to missing outcome data
The study was judged to give rise to some concerns regarding incomplete outcome data.85 This related to high and varying levels of attrition between trial arms. Reasons for non-participation were reported and there did not appear to be any notable differences between those completing the 24 months’ assessment and those lost to attrition by demographic characteristics, initial melanoma diagnoses or time since diagnosis, as reported in the study results.85 Reasons for not attending follow-up were reported as ‘not learning anything new,’ ‘no change in pigmented lesion’ and ‘too far to travel’. Attrition reduces the ability of the study to detect a difference, should one exist.
Bias in selection of reported results
The study was assessed as having a low risk of selective reporting because the trial protocol was available as a trial registration on ClinicalTrials.gov and as a peer-reviewed manuscript. All prespecified outcomes were reported in the results.
Publication bias
We were unable to assess whether or not there was any publication bias because there was only a single study was included. However, we carried out comprehensive searches to reduce the risk of missing relevant studies.
Assessment of clinical effectiveness
Although three publications (including a conference abstract) reporting two RCTs were eligible for this systematic review,23,85,88 they did not report data for stage I patients separately. Authors were contacted to provide further data, which we obtained for stage I melanoma patients from the authors of the study by Robinson et al.85
We were unable to conduct a meta-analysis as only one RCT met the inclusion criteria. We were unable to assess reporting biases using funnel plots or to conduct any subgroup or sensitivity analyses. Thus, data on effectiveness and safety from the included RCT were tabulated and presented in the summary of findings table () and narratively summarised. For outcomes of interest, we have calculated and reported the magnitude of effect.
The primary outcome of the study by Robinson et al.85 was the frequency of SSE by patient–partner dyads. The secondary outcome (among those post resection of stage 0–IIB melanoma) was detection of a new or recurrent melanoma by the dyad or physician. For those post resection of stage I melanoma, the population of interest in this review, data were provided by the study’s author. New primaries, recurrences or metastases were detected in 49 out of 258 (19%) patients with stage IA or IB melanomas post resection of a primary melanoma followed up for up to 24 months. Data were not split by whether the disease was a new primary or recurrence, and recurrences could be at different stages from the original primaries. The types of melanomas identified were melanoma in situ, stage IA, superficial spreading, lentigo maligna and melanomas of ≥ 0.1 mm.
There was no evidence of a difference between intervention and control arms in the proportion of patients with stage IA or IB melanomas in which a new primary or recurrence was detected in this subset (RR 0.75, 95% CI 0.43 to 1.31). However, imprecision affects our certainty of this finding and more evidence is needed to draw any conclusions.
The authors85 concluded that patients with melanoma and their partners reliably performed SSE after participating in a structured skills training programme lasting approximately 30 minutes, with reinforcement every 4 months by the study dermatologist. No conclusions were drawn by the study authors85 about how new primaries or recurrences were detected.
Discussion
Summary of review of different surveillance strategies
This review sought evidence about the relative effectiveness of surveillance and follow-up strategies to identify melanoma recurrence, new primary tumours and metastases in stage I cutaneous melanoma patients following surgical excision of the primary tumour. Only two RCTs (reported in three papers)23,85,88 were eligible and we could obtain data on stage I patients from only one of them.85 This study suggested that an educational intervention for patients and their partners improved self-identification of new primaries, regardless of whether it was delivered in person, through a workbook or via a tablet. However, among the subset of author-provided data on patients post resection of a stage IA or IB melanoma, there was no evidence of a difference in detection of a new primary tumour, recurrence or metastases between those undergoing SSE surveillance and those receiving usual follow-up.
This evidence is of low certainty according to GRADE because of the small number of studies and limited number of available relevant outcome data;86 it is probable that the results of this review would change with the addition of new eligible studies. The certainty of the evidence was downgraded for imprecision, sparse data and a low event rate and for concerns regarding risk of bias. At present, evidence is based on just a single study85 (n = 258 participants) and the evidence is incomplete and offers only internal validity as it was set in the USA. Only one of the prespecified outcomes (new primary or tumour recurrence) in our review was reported, meaning that there are complete gaps in the evidence in this area in terms of overall survival, progression-/recurrence-free survival and detection of recurrence (see ).
As stage I is the most common stage at melanoma diagnosis, it is critical to understand the most effective method of surveillance following treatment. This review demonstrates that current evidence is insufficient and uncertain, so further robust RCTs are required, measuring recurrence and metastases, in addition to overall survival, as outcomes, to establish the most effective surveillance strategy. No assessment of surveillance strategies among those post resection of a stage I melanoma using clinical review, imaging, or diagnostic biopsy as the main component of the strategy were identified.
Strengths and limitations
To our knowledge, this is the first systematic review of surveillance or follow-up strategies for AJCC stage I melanoma. The review followed procedures set out by the Cochrane Collaboration for conducting systematic reviews of RCTs and non-randomised studies, and was robust.82 We conducted comprehensive searches of bibliographic databases and grey literature. All stages of the review, involving screening, data extraction and assessment of risk of bias, were conducted by at least two researchers, either in duplicate or by one researcher with checks by a second researcher. We assessed the risk of bias using the Cochrane Collaborations’s RoB 2.0 tool.83 We contacted authors from both studies to provide further information on participants’ staging of melanoma and obtained data for stage I patients from one study.85 We excluded the majority of potentially relevant primary full-text articles because they were non-comparative or did not assess surveillance strategies.
Because the single included study85 was conducted in a single country, the USA, the findings could be limited in applicability and generalisability. The assessment of risk of bias revealed an overall judgement of ‘some concerns’ due to attrition in the trial at 24 months.85 Publication bias could not be investigated because of the number of studies identified, but the possibility should be considered as there may be studies that did not find positive results and remain unpublished.
Impact and implementations
Evidence for the effectiveness of surveillance and follow-up strategies for stage I melanoma is limited. A previous systematic review sought to identify the range of stage-specific surveillance practices for melanoma patients (any stage) and concluded that surveillance strategies vary around the world during the first 5 years post treatment.25 Our review had narrower inclusion criteria with respect to study design and staging of melanoma. The paucity of this evidence in our review makes it difficult to make recommendations regarding the effectiveness of surveillance and follow-up strategies for stage I melanoma in the UK.
Conclusion
This review demonstrates that evidence for the effectiveness of surveillance strategies is poor for stage I melanoma patients. We were able to obtain data specific to stage I patients from only one of two included studies. This study suggested that an educational intervention encouraging SSE by patients and their partners might be promising and effective overall in increasing SSE and detection of new or recurrent disease by the patient–partner dyads. However, for patients with stage I disease, there was little evidence of benefit of the intervention, compared with control, for detecting new or recurrent disease.
The findings of this review are not wholly unexpected, given the assessment of the existing guidelines for surveillance of stage I disease presented in Chapter 2. What the work presented in both this chapter and Chapter 2 illustrates is the paucity of data on which existing strategies are based on and it raises questions as to whether or not, or how, alternative strategies may be better than current practice. The following chapters go on to consider whether or not alternative strategies for surveillance could be developed. Chapter 4 begins this process by considering the evidence base for approaches to identify those people with stage I disease who might be more at risk of recurrence and, consequently, where there may be more merit in adopting a more intensive surveillance strategy, rather than a less intensive strategy.
