Skin-sparing mastectomy for the treatment of breast cancer

  • Protocol
  • Intervention



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

To assess the efficacy and safety of skin-sparing mastectomy for the treatment of breast cancer.


Description of the condition

Breast cancer is the most frequent non-skin cancer in women (23% of all cancers in women) with an estimated 1.68 million new cases and more than 522,000 deaths reported worldwide in 2012 (GLOBOCAN 2012).

Description of the intervention

Skin-sparing mastectomy was first described in 1991 by Toth and Lappert (Toth 1991) in an effort to maximize skin preservation, remove the nipple-areola complex, improve cosmetic outcome and facilitate reconstruction. In theory, this technique removes an equivalent amount of breast tissue and nipple-areola complex as in radical modified mastectomy described by Madden in 1965 (Madden 1965) but preserves all the skin envelope. Currently, no international practice data are available detailing the frequency of skin-sparing mastectomy versus breast-conserving surgery.

How the intervention might work

Skin-sparing mastectomy greatly enhances the aesthetic results of immediate breast reconstruction by preserving the skin envelope and the natural inframammary fold (Carlson 1996; Cunnick 2004; Patani 2008; Singletary 2003). When skin-sparing mastectomy is undertaken with immediate breast reconstruction, it is possible to minimize costs and the need for further surgeries to reach a good aesthetic result (Gerber 2009).

Why it is important to do this review

The surgical management of breast carcinoma has evolved during the past two decades, and the improvement in techniques has meant that more conservative surgery and better cosmetic procedures can be achieved without compromising oncological safety (Morrow 2002). Surgical strategies have changed significantly, and the objective of modern breast cancer surgery is to maintain oncological efficacy and reduce the number of radical procedures with the goal of minimizing the patient's physical and psychological trauma (Al-Ghazal 2000). The conservative approach and selective lymphadenectomy according to sentinel lymph node biopsy are examples of this progressive evolution (Cody 2001; Giuliano 1997; Lyman 2005; Veronesi 1990).

Despite improved early detection and evidence related to the efficacy of breast-conserving treatment, in some situations, more radical procedures are still indicated. Conventional surgical therapy in these situations is radical modified mastectomy (Madden 1965). Recently, less radical mastectomies, such as skin-sparing mastectomy, have been proposed as a substitute for conventional mastectomy in selected patients for the treatment of breast cancer.

Reports have characterized the histological characteristics of skin flap specimens following skin-sparing mastectomy. This includes identifying residual breast tissue or positive superficial margins, which carry concern for oncological safety and equivalence in maintaining local control. Torresan et al analysed the amount of residual breast tissue after skin-sparing mastectomy by histologically analyzing skin flap specimens and found that 59.5% of specimens contained residual breast tissue, and 9.5% of skin flaps sheltered residual disease (Torresan 2005a; Torresan 2005b). In addition, when skin flaps were > 5 mm, they were associated with the presence of residual disease (Torresan 2005a; Torresan 2005b). Horiguchi et al defined close margins as being within 5 mm and did find margin status significant on multivariate analysis of age, hormone receptor-positive lymph node metastasis, and clinical stage (Horiguchi 2006). Medina-Franco et al examined the incidence of local recurrence (LR) and factors associated with it in a population of participants who underwent skin-sparing mastectomy and immediate reconstruction for invasive carcinoma. Under univariate analysis, the factors associated with higher LR rate were tumor stage II or III, tumor size larger than 2 cm, node-positive disease, and poor tumor differentiation. Actuarial one-, three-, and five-year overall survival rates were 98%, 94%, and 88%, respectively, but under multivariate analysis, factors associated with decreased survival were advanced stage and the absence of hormone therapy (Medina-Franco 2002).

Despite these findings, numerous studies have determined that skin-sparing mastectomy is an oncologically safe procedure with no significant difference in LR compared with conventional mastectomy. The incidence of local recurrence in these data derived from nonrandomized studies ranges from 0 to 7% (Carlson 2003; Carlson 2007; Gerber 2009; Kroll 1999; Langstein 2003; Medina-Franco 2002; Newman 1998; Slavin 1998; Spiegel 2003). These studies include both prospective and retrospective designs and are difficult to compare, as they vary largely in participant sample size, stage of disease, tumor characteristics, adjuvant chemotherapy or radiation therapy, use and type of immediate or delayed reconstruction, and follow-up time (Tokin 2012). In 2010, a meta-analysis of observational studies until 2009 concluded that skin-sparing mastectomy is an oncologically safe procedure. No significant difference in local recurrence was noted between skin-sparing mastectomy versus non–skin-sparing mastectomy groups (seven studies, 3436 participants, 6.2% vs 4.0%, odds ratio 1.25, 95% CI 0.81 to 1.94), and no significant heterogeneity was noted between the studies. The skin-sparing mastectomy group had a lower proportion of distant relapses compared with the non–skin-sparing mastectomy group (five studies, 2122 participants, 10.0% vs 12.7%, odds ratio 0.67, 95% CI 0.48 to 0.94), but this should be interpreted with caution because the grade of the tumors was not adequately reported in the studies considered (Lannitis 2010).

Despite these data, a new systematic review is necessary to include updated data concerning the efficacy of skin-sparing mastectomy and to evaluate its oncological safety and the quality of life in women who have had this type of surgery.


To assess the efficacy and safety of skin-sparing mastectomy for the treatment of breast cancer.


Criteria for considering studies for this review

Types of studies

We will search for randomized controlled trials (RCTs), as they provide the highest level of evidence.

If no RCTs are found, we will expand our criteria to include nonrandomized comparative studies (cohort and case-control studies).

Types of participants

Women with a diagnosis of ductal carcinoma in situ or invasive breast cancer according to the histopathological criteria of the World Health Organization (Tavassoli 2003), regardless of age, time of onset, or disease stage.

Types of interventions

Skin-sparing mastectomy (ie, removal of all breast tissue and the nipple-areola complex and preservation of the entire skin) compared with radical modified mastectomy (ie, removal of the skin that overlies the breast including the nipple and areola) for the treatment of ductal carcinoma in situ or invasive breast cancer, regardless of adjuvant therapy.

In this review, only women who have had breast reconstructive surgery will be included.

Types of outcome measures

Primary outcomes
  • Overall survival: defined as the proportions of survivors in the studied and followed-over periods, and considered separately for ductal carcinoma in situ and early breast cancer.

Secondary outcomes
  • Local recurrence incidence rate and time-to-event for recurrence during the follow-up period, and considered separately for ductal carcinoma in situ and early breast cancer.

  • Adverse events: local surgical complications or systemic surgical complications such as thromboembolic events.

    • Short-term outcomes.

      • Local complications.

        • Explantation of implant/expander.

        • Hematoma.

        • Seroma.

        • Rehospitalization.

        • Skin necrosis (nipple, areola, or flap necrosis).

        • Skin necrosis with revisional surgery.

        • Infection.

    • Long-term outcomes.

      • Capsular contracture of the implant.

  • Cosmetic results: using the BREAST-Q (Breast-Q) questionnaire. If no validated instruments are included in the studies, participant and professional opinion will be documented.

  • Quality of life and participant satisfaction: using the EORTC QLQ-BR23 (Fayers 1999) and BREAST-Q (Breast-Q) questionnaires. If studies do not include validated instruments, a narrative description of participant opinion will be provided.

Search methods for identification of studies

Electronic searches

We will search the following databases.

Searching other resources

Bibliographic searching

We will try to identify further studies from reference lists of identified relevant trials and reviews. A copy of the full article for each reference reporting a potentially eligible trial will be obtained. When this is not possible, attempts will be made to contact study authors to request additional information.

Data collection and analysis

Selection of studies

Two review authors (BS and MDR) will independently examine the titles and abstracts of articles identified in the search as potentially relevant trials. After this initial assessment, we will obtain full versions of all potentially relevant articles. We will consult a third review author (JLBB) to help resolve disagreements. Excluded studies will be recorded in the "Characteristics of excluded studies" table. Studies published only in English will be included.

Data extraction and management

We will extract and record data on data extraction forms, which we will develop. Two review authors (BS and MDR) will independently undertake full data extraction and will consult a third review author (JLBB) to help resolve disagreements. For those studies with more than one publication, we will extract data from all publications, and the version with the longest follow-up will be considered. We will seek unpublished data concerning outcomes of interest from authors by letter, as stated above. We will enter references into Review Manager 5 software (RevMan).

We will include the following information from individual studies on data extraction forms.

  • Publication details.

  • Study design, study setting, inclusion/exclusion criteria, methods used to control for confounders, adjusted and unadjusted outcome measures.

  • Participant population (eg, age, type of surgical procedure, tumor stage, grade of tumor, molecular subtypes).

  • Details of interventions.

  • Outcome measures.

  • Withdrawals, length and method of follow-up, and number of participants followed up.

We will enter quantitative data into RevMan software (RevMan) to carry out the analyses.

Assessment of risk of bias in included studies

Assessment of the methodological quality of each study will be undertaken independently by two review authors (BS and RR), as per the data extraction process described in the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (Higgins 2011).

Appraisal will follow The Cochrane Collaboration's risk of bias (RoB) tool (Higgins 2011), the EPOC risk of bias criteria (Cochrane EPOC 2013), and recommendations by Norris et al (Norris 2013). Risk of bias will be assessed under the following domains: selection bias, performance/detection bias, attrition bias, reporting bias, and other bias. For each RoB domain and its associated specific questions outlined below, review authors will assign "high risk," "low risk," or "unclear risk."

Selection bias
  • Was the allocation sequence adequately generated?

Score "low risk" if a random component in the sequence generation process was described (eg, referring to a random number table). Score "high risk" when a nonrandom method was used (eg, performed by date of admission). Nonrandomized studies should be scored "high risk." Score "unclear risk" if not specified in the paper.

  • Was the allocation adequately concealed?

Score "low risk" if participants and investigators enrolling participants could not foresee assignment (eg, because a centralized randomization scheme, an on-site computer system, or sealed opaque envelopes were used). Nonrandomized studies should be scored "high risk." Score "unclear risk" if not specified in the paper.

For nonrandomized studies the following questions should also be assessed.

  • Were baseline outcome measurements similar?

Score "low risk" if performance or participant outcomes were measured before the intervention was provided and no important differences were present across study groups. Score "high risk" if important differences were present and were not adjusted for in the analysis. Score "unclear risk" if not specified in the paper.

  • Were baseline characteristics similar?

Score "low risk" if baseline characteristics of the study and control providers were reported and similar. Score "unclear risk" if this was not clear in the paper (eg, characteristics were mentioned in the text, but no data were presented). Score "high risk" if no report of characteristics was provided in text or tables or if differences between control and intervention providers were noted.

  • Was adequate adjustment for confounding provided?

Score "low risk" if appropriate methods were used to adjust for potential confounding. Score "Unclear risk" if the methods used to adjust for confounding were not reported in the paper. Score "High risk" if potential confounding from the following variables was not addressed: adjuvant radiotherapy, age, surgical techniques, stage of disease, ductal carcinoma in situ or invasive breast cancer, and chemotherapy.

Performance/detection bias
  • Was knowledge of the allocated interventions adequately prevented during the study?

Score "low risk" if the study authors stated explicitly that the primary outcome variables were assessed blindly or if the outcomes were objective (eg, length of hospital stay). Score "high risk" if the outcomes were not assessed blindly. Score "unclear risk" if not specified in the paper.

Attrition bias
  • Were incomplete outcome data adequately addressed?

Score "low risk" if missing outcome measures were unlikely to bias the results (eg, reasons for missingness unlikely to be related to true outcome, missing outcome data balanced in numbers across intervention groups with similar reasons for missing data, or missing data imputed using appropriate methods). Score "high risk" if missing outcome data were likely to bias the results. Score "unclear risk" if not specified in the paper.

Reporting bias
  • Were reports of the study free from selective outcome reporting?

Score "low risk" if no evidence suggests that outcomes were selectively reported (eg, the study had a protocol prespecifying the outcomes, all relevant outcomes in the methods section are reported in the results section), Score "high risk" if some prespecified outcomes were subsequently omitted from the results. Score "unclear risk" if not specified in the paper.

  • Were reports of the study free from selective analysis reporting?

Score "low risk" for each outcome if no evidence suggests that analyses were selectively reported (eg, analyses were defined in the methods section of the protocol or paper). Score "high risk" if evidence suggests selective analysis reporting (eg, multiple adjusted analyses have been carried out and only one reported, unusual cut-points have been used for categorizing an outcome). Score "unclear risk" if unclear from the paper.

Classification of study designs—study designs that may be included and defined as follows
  • Prospective cohort study: groups of exposed and nonexposed individuals that have been followed over time to compare incidence (or rate of death from disease) between groups (Gordis 1996). In prospective cohort studies, recruitment, exposure/intervention, and outcomes must all have occurred after the study was set up.

  • Retrospective cohort study: groups of exposed and nonexposed individuals that have been followed over time to compare incidence (or rate of death from disease) between groups (Gordis 1996). In retrospective cohort studies, outcomes must have occurred before the study was set up or must have been collected afterward, or both.

  • Case-control study: a study that compares people with a specific outcome of interest (cases) versus people from the same source population but without that outcome (controls), to examine the association between outcome and prior exposure.

Measures of treatment effect

We will report time-to-event outcomes (eg, overall survival, local recurrence) as hazard ratios with 95% confidence intervals (CIs). If necessary, hazard ratios will be estimated using the methods of Parmar et al (Parmar 1998). If it is not possible to estimate hazard ratios from all studies, the number of events (eg, deaths, recurrences) over five years and ten years of follow-up will be treated as dichotomous outcomes.

We will report dichotomous outcomes (eg, recurrence, distant disease, explantation of implant/expander, hematoma, seroma, rehospitalization, skin necrosis [nipple, areola, or flap necrosis], skin necrosis [nipple, areola, or flap necrosis] versus revisional surgery, infection, and cosmetic results) as risk ratios (RRs) and risk differences (RDs) with 95% CIs. We will pool the data for meta-analysis using the pooled log-RR, when appropriate. We will report continuous outcomes (eg, quality of life) as mean differences (MDs) with 95% CIs.

Given the current approach for ductal carcinoma in situ or invasive breast cancer, it seems reasonable to consider the treatment effect and reading the primary outcome as a noninferiority question. Thus, the noninferiority bound for the hazard ratio will be 1.13 (based on a 10-year survival rate of 24% for conventional mastectomy with a cutoff value of 27% for skin-sparing mastectomy). For local recurrence, the noninferiority bound for the hazard ratio will be 2.67 (based on 3% 10-year local recurrence for conventional mastectomy with a cutoff value of 8% for skin-sparing mastectomy).

Unit of analysis issues

We anticipate that the appropriate unit of analysis will be the individual participant, rather than the surgical unit, hospital, or center.

Dealing with missing data

When data are missing or are unsuitable for analysis (eg, intention to treat is not used), we will contact the study authors to request further information. When data are missing to the extent that the study cannot be included in the meta-analysis and attempts to retrieve data have been exhausted, we will present the results in the review and will discuss the context of the findings.

Assessment of heterogeneity

If appropriate, we will assess statistical heterogeneity using the Chi2 statistic (Cochran 1954). We will also assess heterogeneity between studies using the I2 statistic to examine the percentage of total variation across studies due to heterogeneity rather than chance. An I2 value of 30% to 60% may represent moderate heterogeneity, and values greater than 50% may be considered to show substantial heterogeneity (Higgins 2003).

We will investigate factors as potential causes of heterogeneity in the included studies using the framework below (χ2 or Chi2).

  • Clinical diversity: includes study location and setting, full characteristics of participants, comorbidities, and treatments that participants may be receiving on trial entry. We will consider how outcomes were measured, the definitions of outcomes, and how they were recorded. Depending on the extent of clinical diversity, we will analyze studies separately or will present the results using a narrative approach.

  • Methodological diversity: includes assessment of the randomization process, study quality, and analytical method.

Assessment of reporting biases

We will search for protocols of included trials using PubMed (National Library of Medicine) and other trial registries, when possible. We will contact study authors to attempt to establish a full data set or reasons for the nonreporting of certain outcomes.

Data synthesis

We will synthesize data using RevMan (RevMan). We will base the selection of fixed-effect or random-effects models for data synthesis on a number of factors. When significant clinical or methodological heterogeneity exists, we will use a random-effects model. Otherwise, we will use the fixed-effect model.

We will combine data using the inverse variance method on the log-HR scale for time-to-event outcomes, on the log-RR scale for dichotomous outcomes, and on the MD scale for continuous outcomes. For random-effects meta-analysis, we will use the DerSimonian and Laird method.

When the data are too diverse to permit combining of effect sizes in a meaningful or valid manner, we will present the results of individual studies in table and graphical formats and will use a narrative approach to summarize the data.

Subgroup analysis and investigation of heterogeneity

As we expect a small number of published studies, we do not envisage that it will be possible to perform subgroup analyses. However, we would like to consider the following subgroups.

  • Participants who received adjuvant radiotherapy versus participants who did not receive radiotherapy.

  • Younger (< 50 years of age) versus older (≥ 50 years of age) women.

  • Cancer stage as per TNM (size and/or extent of the primary tumor [T], amount of spread to nearby lymph nodes [N], and presence of metastasis [M] or secondary tumors) classification system (NCI 2013).

  • Systemic therapy (chemotherapy or endocrine therapy) versus no systemic therapy.

  • Molecular subtype.

Sensitivity analysis

We will conduct sensitivity analyses by excluding trials (1) of low methodological quality, (2) with a small sample size, and (3) with short follow-up. We will consider and discuss the results of these analyses in comparison with overall findings.


The authors wish to thank all members of the Cochrane Breast Cancer Group and Amy K Alderman for their hard work in editing and reviewing the protocol.


Appendix 1.



OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR (doubl* AND blind*) OR (singl* AND blind*) OR assign*OR allocat* OR volunteer* OR 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'randomized controlled trial'/exp OR'single blind procedure'/exp


'case control study'/syn OR ('case control' OR 'case base' OR 'case matched' OR retrospective) NEXT/3 (analys* OR design* ORevaluation* OR research OR stud* OR survey* OR trial*)


(cohort OR concurrent OR incidence OR longitudinal OR followup OR 'follow up' OR prospective OR retrospective) NEXT/1 (analys* OR design* OR evaluation* OR research OR stud* OR survey* OR trial*) OR 'prospective method'/exp OR 'retrospective study'/syn


'breast cancer'/exp


'mastectomy'/exp OR mastectomy


'skin-sparing mastectomy'


'segmental mastectomy'/exp OR 'segmental mastectomy'


'breast conserving surgery'/exp OR 'breast conserving surgery'


'partial mastectomy'/exp OR 'partial mastectomy'


'lumpectomy'/exp OR lumpectomy


#5 OR #6 OR #7 OR #8 OR #9 OR #10


'radical modified mastectomy'


'subcutaneous mastectomy'/exp OR 'subcutaneous mastectomy'


#12 OR #13


#11 AND #14


(mastectomy OR mastectomies) NEAR/5 ('skin-sparing' OR segmental OR partial OR subcutaneous OR 'radical modified')


#15 OR #16


#4 AND #17


'animals'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR'nonhuman'/exp


'human'/exp OR 'normal human'/exp OR 'human cell'/exp


#19 AND #20


#19 NOT #21


#18 NOT #22


#23 AND #1


#23 AND #2


#23 AND #3


#24 AND [embase]/lim


#25 AND [embase]/lim


#26 AND [embase]/lim

Appendix 2. MEDLINE

# ▲ Searches
1randomized controlled
2controlled clinical
5clinical trials as
81 or 2 or 3 or 4 or 5 or 6 or 7
9Case-Control Studies/
10Control Groups/
11Matched-Pair Analysis/
12retrospective studies/
13((case* adj5 control*) or (case adj3 comparison*) or control group*).ti,ab.
149 or 10 or 11 or 12 or 13
15cohort studies/
16longitudinal studies/
17follow-up studies/
18prospective studies/
19retrospective studies/
2415 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23
25exp Breast Neoplasms/
26exp Mastectomy/
28exp Mastectomy, Segmental/
30breast conserving
3326 or 27 or 28 or 29 or 30 or 31 or 32
34exp Mastectomy, Modified Radical/
35exp Mastectomy, Subcutaneous/
3734 or 35 or 36
3833 and 37
39(mastectom* adj5 (skin-sparing or segmental or partial or subcutaneous or radical modified)).mp.
4038 or 39
4125 and 40
4442 not 43
4541 not 44
468 and 45
4714 and 45
4824 and 45

Appendix 3. CENTRAL

#1 MeSH descriptor: [Breast Neoplasms] explode all trees

#2 MeSH descriptor: [Mastectomy] explode all trees

#3 MeSH descriptor: [Mastectomy, Segmental] explode all trees

#4 skin-sparing mastectomy or breast conserving surgery or partial mastectomy or lumpectomy

#5 #2 or #3 or #4

#6 #1 and #5

Appendix 4. LILACS

Search strategy
#1(Mastectomia Segmentar) OR  (Mastectomia Segmental ) OR (Mastectomy, Segmental ) OR (Lumpectomy) OR (Partial Mastectomy) OR (Breast-Conserving Surgery) OR (Ex E04.466.701)
#2(Mastectomy, Subcutaneous) OR (Mastectomia Subcutânea) OR  (Mastectomia Subcutânea)  OR (Ex E04.466.823)
#3(Breast Neoplasms) OR  (Neoplasias de la Mama) OR (Neoplasias da Mama) OR (Cancer of Breast) OR (Breast Cancer) OR (Breast Tumors)  

Appendix 5. WHO ICTRP

Basic search

1. Skin-sparing mastectomy for the treatment of breast cancer

2. Breast cancer AND skin-sparing mastectomy

Advanced searches

1. Title: Skin sparing mastectomy for the treatment of breast cancer

Recruitment status: all

2. Condition: breast cancer

Intervention: skin-sparing mastectomy OR mastectomy OR breast conserving surgery OR segmental mastectomy

Recruitment status: all

3. Condition: breast cancer

Intervention: nipple AND areola AND mastectomy

Recruitment status: ALL

Appendix 6.

Basic search

1. Skin-sparing mastectomy for the treatment of breast cancer

2. Breast cancer AND skin-sparing mastectomy

 Advanced searches

1. Title: Skin sparing mastectomy for the treatment of breast cancer

Recruitment: all studies

Study results: all studies

Study type: all studies

Gender: all studies

2. Condition: breast cancer

Intervention: skin-sparing mastectomy OR mastectomy OR breast conserving surgery OR segmental mastectomy

Recruitment: all studies

Study results: all studies

Study type: all studies

Gender: all studies

3. Condition: breast cancer

Intervention: nipple AND areola AND mastectomy

Recruitment: all studies

Study results: all studies

Study type: all studies

Gender: all studies

Contributions of authors

  • Draft the protocol: BS, RR, JLBB, JB

  • Perform study selection: BS, MDR

  • Extract data from studies: BS, MDR

  • Enter data into RevMan: BS

  • Carry out the analysis:BS, JB

  • Interpret the analysis: BS, RR, JLBB, JB

  • Draft the final review: BS

  • Resolve disagreements: JLBB

  • Update the review: BS

Declarations of interest

None known.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • None, Not specified.