Nonmelanoma skin cancers (NMSCs), also known as keratinocytic skin cancers constitute the most common malignancy in the United States and the world.1 It has been estimated that about 3.5 million of these cancers are diagnosed every year in the United States alone – 2.8 million basal cell carcinomas (BCCs) and 700,000 squamous cell carcinomas1 (SCCs), which are the two most common subtypes of NMSCs. Other subtypes of this group of cancers include cutaneous lymphomas, adnexal tumors, Merkel cell carcinomas and other rare primary cutaneous neoplasms.2 Although grouped together, BCCs and SCCs have clear differences relating to their cause, pathogenesis, clinical course and management.
Incidence rates of these cancers are known to be on the rise in many countries. Currently, BCCs, the most common type of NMSCs, account for up to 80% of cases, with an incidence ranging from as low as 47.4 in women from Scotland to 1541 in men from Australia per 100,000 individuals.2,3 Squamous cell carcinomas are the second most common type of NMSC: its incidence per 100,000 individuals ranges from 5.3 in women from Germany to 772 in men from Australia.2 Although the reason for the increased incidence is unclear, it may be linked to increased sun-seeking behaviors,4 and increased patient and physician awareness of the disease, in addition to improved medical coding. By contrast, mortality rates have declined because of increased public education on sun protection and enhanced clinical management;5 however, it remains a relevant patient-centered outcome in cancer management. Basal cell carcinoma is characterized by local invasiveness and destruction which is associated with significant morbidity.6 Squamous cell carcinoma on the other hand has a high metastatic potential and is therefore responsible for the majority of deaths from NMSCs. In addition, these cancers are associated with high recurrence rates and an increased risk of transformation to melanoma.7
Risk factors include exposure to ultraviolet radiation (UVA and UVB), artificial tanning, being fair skinned, having precancerous skin conditions such as actinic keratosis and Bowen's disease, being an older white male, having a history of sun burns or fragile skin, having inherited syndromes such as nevoid BCC syndrome, certain medications, immunosuppression, being infected with the human papilloma virus and having a previous history of radiotherapy.8 Although they are rarely life threatening and highly curable, NMSCs are associated with significant disfigurement when not diagnosed and treated in a timely manner because they frequently affect the head, face and neck region, which are highly visible parts of the body, leading to potentially influential effects in terms of social stigma and the patient's self-esteem.
The primary aim of treatment is to achieve complete extirpation or destruction of the lesion, whereas achieving a good and acceptable cosmetic outcome is an important secondary goal. Choice of treatment depends on several factors, including the clinical and histological nature, size, and site of the lesion; presence of other comorbidities; expertise; and availability and affordability of treatment. Treatment modalities for NMSC include medical and surgical approaches. Medical interventions that have been used successfully include topical 5-fluorouracil, cisplatin, imiquimod, photodynamic therapy with 5-aminolevulinic acid and radiotherapy.8,9 Surgical therapies include surgical excision, curettage with electrodessication, cryotherapy and Mohs micrographic surgery (MMS).
Although NMSC has been successfully managed with the above listed therapies, several shortcomings have been reported in many of these treatment approaches. For instance, electrodessication with curettage has been associated with the formation of hypertrophic “white” scars after the procedure.9 Incomplete margin removal is frequently observed when NMSC is treated with surgical excision coupled with quality of life issues as it relates to aesthetics. Radiotherapy is painless and has been used as an adjunct to surgery; however, it poses a risk of developing additional NMSCs in the irradiated field over time.10 The use of topical 5-fluorouracil is somewhat limited to the treatment of superficial NMSCs such as actinic keratosis because of its inability to achieve adequate penetration in invasive cases.11,12 Mohs micrographic surgery is an important surgical alternative to the above treatment approaches and is known to produce improved cosmetic results. However, no prior review has focused on examining the clinical effectiveness of MMS in the management of NMSC compared with these other known treatment modalities.
Mohs micrographic surgery is a staged procedure that involves the sequential removal of successive layers of tissue, with microscopic analysis and mapping of horizontally oriented frozen sections of all surgical margins. It is thought to provide the best long-term cure rate for any cutaneous SCC.13 Two important advantages of this procedure are the ability to excise subclinical tumors extension as in the case of a perineural involvement, and complete assessment of tissue margin during surgery, which minimizes tumor recurrence rates. It also allows for optimal aesthetics and improved functional outcome because of tissue conservation.13 Some of the limitations of MMS include the requirement for specialized training for healthcare providers, patient inconvenience because of the prolonged duration of the procedure, and treatment costs associated with the procedure. Although MMS is not always employed because of limited resources, the extended period of follow-up, high rates of recurrence and the cost of dealing with recurrences over time inadvertently increases the cost of treating NSMC with other modalities.
A comprehensive search of the Cochrane Library, the JBI Database of Systematic Reviews and Implementation Reports and Google Scholar yielded no systematic review on the effectiveness of MMS in the treatment of NMSC compared with other treatment modalities. A previous systematic review to compare the effectiveness, cost and complications of MMS and surgical excision in the treatment of periorbital BCCs yielded no reliable conclusions as no studies were found to meet the review's inclusion criteria.14 Another systematic review explored various treatment options in the management of primary BCCs;15 however, the review did not explicitly seek to determine effectiveness of MMS as compared with all other treatments for NMSC, which is the focus of our research question. It was therefore concluded that no existing systematic review reports or protocols address the specific proposed research question. A preliminary search of the literature indicates the availability of relevant published studies, which may be included in this review.16-22 This review will seek to evaluate both published and unpublished literature to synthesize the evidence on the effectiveness of MMS for the treatment of NMSC.
Types of participants
The review will consider studies that include participants with an established diagnosis of NMSC. For the purposes of this review, an established diagnosis of NMSC will consist of either SCC or BCC, confirmed histologically. Studies will be excluded if participants had undergone MMS for an unknown diagnosis or any diagnosis not related to NMSCs.
Types of interventions
The review will include studies in which MMS was the modality of therapy.
Studies that compared the effectiveness of MMS with other treatment modalities such as, but not limited to, surgical excision, curettage and electrodessication, radiotherapy, topical 5-fluorouracil and imiquimod immunotherapy will be considered.
Primary outcomes: Mortality and recurrence rates of NMSCs. All time frames for mortality and recurrence (one year, three year, five year or ten year) will be reported.
Secondary outcomes: Quality of life measures such as suboptimal aesthetics (scarring, disfigurement), frequency of adverse events or complications after treatment, worry of future skin cancers, anxiety and self-consciousness are usually associated with these cancers.7
Types of studies
The review will consider studies that include the use of MMS in one group, and at least one other control or comparator group using other treatment options. Study designs such as experimental designs (i.e. randomized controlled trials, clinical controlled trials, and quasi-experimental studies), observational designs (i.e. longitudinal prospective cohort studies and retrospective cohort studies such as case-control studies) as well as epidemiological designs (i.e. cross-sectional studies) with control or comparator groups will be included. Studies which combine two or more therapies will be excluded.
A three-step search strategy will be utilized in this review. An initial limited search of Ovid MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract and the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Third, the reference list of all identified reports and articles will be searched for additional studies. Although MMS was not fully endorsed until 1985, it was well known in the clinical community as early as 1969.20 Thus, this review will consider studies as far back as 1969 for inclusion as this is the earliest recorded date of the procedure being introduced into practice. Studies not written in English language will be excluded. The following databases will be searched:
Ovid MEDLINE (Medical Literature Analysis and Retrieval System Online),
CINAHL (Cumulative Index to Nursing and Allied Health Literature),
Embase (Excerpta Medica Database),
CENTRAL (Cochrane Central Register of Controlled Trials),
ClinicalTrials.gov (www.clinicaltrials.gov) and the,
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en).
The search for unpublished studies will include:
NYAM (New York Academy of Medicine),
PQDT (ProQuest Dissertations & Theses Database).
Initial keywords to be used will be:
Skin cancer, skin neoplasm, skin tumor, skin growth, nonmelanoma skin cancer, NMSC, squamous cell carcinoma, SCC, basal cell carcinoma, BCC, cutaneous BCC or cBCC
Mohs, Mohs surgery, Mohs micrographic surgery, MMS, micrographic surgery or microsurgery
Surgery, surgical excision, radiation therapy, radiotherapy, curettage, electrodesiccation, 5-fluorouracil therapy, topical fluorouracil, imiquinod or immunotherapy
Recurrence rate, complication, adverse event, disfigurement, functional limitation, mortality, quality of life, incidence or prevalence.
Selection of studies
Studies retrieved from the search will be compared by authors’ names, date of study, location and name of institution, and journal of publication to remove duplicate articles. The process of study selection will include merging search results into Endnote, the screening of title and abstracts to identify and remove irrelevant studies, then retrieval of full text of articles for full review of potentially relevant studies.
Assessment of methodological quality
Studies meeting the inclusion criteria will be assessed for their methodological quality to examine bias using the Joanna Briggs Institute Meta-analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) critical appraisal instruments (Appendix I, Appendix II, Appendix III) by two reviewers independently. Any disagreement that may arise will be settled by discussion with a third review author. The risk of bias level will be recorded for each critical appraisal question instead of using a cutoff to determine methodological quality. The influence of each type of risk of bias for the same outcome will be explored during the meta-analysis, however, if this cannot be performed, the risk of bias levels will be discussed in the narrative synthesis.
Data will be extracted from studies included in the review using the JBI-MASTARI data collection tool (Appendix IV) by two reviewers independently to minimize bias. The data to be extracted will include the following:
- Patients’ demographics: age, sex, histological evidence of NMSC and number randomized to each group or number in each cohort.
- Methods: inclusion and exclusion criteria and other aspects of study design.
- Interventions: types and description of other treatment modalities, and duration, route and frequency of administration.
- Outcomes: the time to recurrence of NMSC, mortality rate, frequency of adverse events and score on validated quality of life tools.
- Results: Statistical methods used, including intention to treat, means, standard deviation and event rates.
Data synthesis will be carried out using the JBI-MAStARI software (Joanna Briggs Institute, Adelaide, Australia), or Comprehensive Meta-analysis (CMA) Version 3 (Biostat, Inc, New Jersey, United States of America), as appropriate. The unit of analysis for this review will include all individual studies that meet the inclusion criteria. Assessment of heterogeneity will be carried out to ascertain that there is sufficient homogeneity between studies to allow for meta-analysis using a random effects model. An I 2 value greater than 75% will be considered too high for performing meta-analysis. All outcome estimates/effect sizes in this review will be expressed as proportions, odds ratios, risk ratios or means depending on the study designs and level of measurement of the outcome. In the presence of substantial statistical heterogeneity, a descriptive synthesis will be presented in narrative texts and tables. Subgroup analysis will be carried out to investigate heterogeneity based on the type of NMSC (SCC or BCC) and meta-regression will examine the influence of time frames on the effect size. However, meta-regression will not be considered if less than ten studies are included in the meta-analysis.23
Appendix I: JBI Critical Appraisal for Experimental Studies
Appendix II: JBI Critical Appraisal Checklist for Comparable Cohort/ Case Control
Appendix III: JBI Critical Appraisal Checklist for Descriptive/ Case Series
Appendix IV: JBI Data Extraction Form for Experimental/Observational Studies
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