Examining the Cosmetic Results, Quality of Life and Patient Satisfaction Achieved With Skin Reducing Nipple Sparing Mastectomy and Implant Based Breast Reconstruction, and Comparing it to Classic Skin- Sparing Mastectomy and Implant- Based Breast Reconstructive Surgeries

Introduction The indication of total breast removal is primarily the part of a correct oncological therapy, but secondly the removal of the full parenchyma can be prophylactic among high risk patients with positive genetic testing. In modern breast surgery, mastectomy means the removal of the entire glandular tissue. Surgery can be done in the absence of contraindication (eg. skin infiltration, mastitis carcinomatosis), by preserving the nipple-areola complex (NAC) and the skin layer above the parenchyma (nipple-sparing mastectomy, NSM) by removal of the whole or a part of the NAC (skin-sparing mastectomy, SSM) or by removal of the nipple but with the preservation of the areola (areola-sparing mastectomy, ASM). It is important to emphasize that similarly to the classic simplex mastectomy in the cases of SSM, ASM and NSM techniques provided by an experienced and qualified breast surgeon, the complete oncological removal of the mammary gland is done\[1\].

The essence of advanced mastectomy techniques is that they ensure the combination of radical oncological resection and immediate (immediate breast reconstruction, IBR) or delayed-immediate breast reconstructive surgery (delayed immediate breast reconstruction, D-IBR) (insertion of a tissue expander during the first operation, then as a second step replace it with a silicone implant). It avoids all the burden and negative effects of distant flap surgery, like donor scars, loss of movements etc. One or two-step post-mastectomy breast reconstructive surgeries are mainly implant-based techniques and less commonly autologous tissue techniques like distant pedicle flaps or free flaps. The tissue expander or silicone implant is placed primarily in a submuscular position but also can be inserted in a subcutaneous position in front of the large pectoral muscle. The coverage of the lower pole or even the entire surface of the implant may be strengthened with biological (so-called acellular dermal matrix) or synthetic materials (Ultrapro mesh) to reduce the pressure load of the implant on the preserved skin, the consequent skin perforation and so the loss of the implant.

The international literature of immediate or delayed-immediate postmastectomy breast reconstructive techniques is extensive and the correlation between these procedures and the oncological treatments (such as adjuvant radiotherapy) are well known \[2\]. According to the currently available evidence, reconstructive techniques do not adversely affect oncological outcome, so these breast surgical techniques are nowadays considered standard procedures in advanced breast cancer surgery\[3\]. Postmastectomy breast reconstruction surgeries are well-known as effective rehabilitation procedures, with significant psycho-oncological benefits to patients with low complication rates and high patient satisfaction. \[4, 5\]. Postmastectomy breast reconstructive surgery however require more sophisticated surgical techniques, special expertise, longer surgical time and significantly higher costs than simplex mastectomies.

Selecting the type of advanced mastectomy (SSM/NSM/ASM) of breast cancer depends on the location of the lesion, the size of the breast and its ptosis. Absolute contraindications of NSM are Paget disease of the nipple, bloody discharge, skin and nipple infiltration. Relative contraindications comprise pendolous/ptotic or large/larger sized breast and a distance between the nipple and tumor of less than 2cm. To achieve best cosmetic results, sparing the NAC became of prime importance, with widespread use of skin-sparing mastectomies. Sparing the skin layer and the NAC during removal of the entire glandular tissue promotes the efficiency of breast reconstruction by avoiding the reduction of projection, nipple reconstruction surgery and nipple tattoo. The cosmetic results and quality of life of those patients who had SSM instead of having NSM due to pendolous/ptotic breast are provenly unfavorable \[6\]. Numerous studies have proven that NSM with proper technique is an oncologically reliable method, hence it has become the part of several international protocols \[7\]. In the case of the high volume pendulous/ ptotic breasts, NSM and optimal implant-based breast reconstruction are achievable only by reduction of the skin-layer of the breast. The optimal surgical technique of skin-reducing nipple sparing mastectomy (SRNSM) has not been standardized yet. Due to the lack of high quality evidence and knowledge relating to the blood supply of NAC, safety of the procedure, complication rate, and oncological radicality the technique has not gained widespread popularity\[8, 9\].

Our present study validates the SRNSM operative technique, and also compares its results to that of classic SSM and delayed- immediate reconstruction in a response- adaptive prospective study.

Aim of the study This is a response-adaptive (RAR) \[10\] prospective randomized study with a long-term follow-up and the aim of this clinical study is to measure with qualitative and quantitative indicators the changes in cosmetic results, quality of life and patient satisfaction after delayed- immediate breast reconstruction with standardized technique Skin Reducing Nipple sparing mastectomy, SRNSM and SSM with standardized horizontal skin incision.

According to our hypothesis, SRNSM with standardized technique on pendulous/ ptotic breasts is a safe procedure compared to SSM. It also promotes the cosmetic efficacy of SRNSM with the removal of the entire glandular tissue through avoidance of the reduction of projection, the need later nipple reconstruction surgery and of areola tattoo.

In our study we propose that compared to one of the well-known and widely investigated studied SSM, our current standardized SRNSM technique is able to perform similar oncologically safe entire gland tissue removal, with low complication rate, accommodating for adjuvant treatments. Furthermore, it may provide superior cosmetic results than SSM (NAC is not removed, projection is maintained, and there is no need for further nipple reconstruction or tattoo) with high patient satisfaction which is maintained long term.

Patients and method Participation in the study is voluntary. In this response-adaptive (RAR) prospective randomized study, the used standardized SSM are considered to be routine procedures in the literature and in our department as well.

According to literature the SRNSM technique in not a widely used procedure. The reconstructive surgery after SSM or SRNSM do not represent new surgical procedures for our patients either in their technique nor in the indication, this prospective trial guarantee quantitative and qualitative data collection only. Applied oncological therapies are unaffected by the study and still follows the decisions of the Institute's preoperative and postoperative multidisciplinary breast cancer committee.

The study does not change the complex oncological treatment in any way compared to the institute's protocol.

Response-adaptive classification in this study means that the choice of the optimal surgical technique for the patient is not affected by the clinical trial. The selection of the surgical technique is based on the decision-making models that we use for a long time (absolute and relative contraindications), and made individually for the patient's oncological disease (eg. nipple removal), locations of the tumor, in accordance of the involvement of the skin and the existence of Paget's disease (SRNSM vs SSM), which is the same way as we treat our patients out-of-study.

Therefore, in a scientific sense, this study does not involve treatments other than routine treatment protocols.

Primary endpoint of the study:

Using correlation analysis to measure objective changes and the changes over time in oncological control, cosmetic results, quality of life and patient satisfaction achieved by different surgical techniques at one, two, three, four, and five years of follow-up.

Secondary endpoints of the study Based on the results of this study, the aim is to determine the rate of early and late postoperative complications, procedural burden (length of the operation, hospitalization).

Patients

\- Under the age of 65 with uni- or bilateral primary breast cancer ( clinical Stage 0-III), needing skin sparing mastectomy, nipple sparing mastectomy or patients require risk reducing mastectomy independently of the axillary surgery, having immediate or delayed-immediate implant based reconstruction.

Exclusion criteria:

* In case the patient does not volunteer for the examination or the follow-ups * Age above 65 years or poor general health condition, where the estimated life expectancies would be less than 2 years even without the tumorous disease * Malignant invasive tumor in the past history (except for non-melanoma skin tumors) * Mastectomy and reconstruction performed due pregnancy associated breast cancer * Prior breast surgery (e.g. aesthetic surgery, mastopexy) and/or radiotherapy on the breast or in the axilla * Malignant tumor is not removed completely with pathological examination * Severe non-surgical (e.g. radiotherapy) complication, which could influence the aesthetic and functional results * Autoimmune diseases * Mastitis carcinomatosa * Lymphangitis carcinomatosa * Open wound therapy due SSI * Long-term steroid usage, which changed the skin's quality and structure * Patient under foster care, or psychically non-cooperative patient

Preoperative examination:

* Physical examination * Triplet examination of the breast * Chest X-ray * Axillary ultrasound with aspiration cytology if needed * Required additional imaging based on the oncological staging (targeted x-ray, CT, MRI, PET) * Routine hematological and blood test analysis * Measurements of jugulum-nipple width, nipple midline width, and nipple inframammary-fold width * Measurement of horizontal and vertical diameter of areola * Regnault Classification of breasts' ptosis * Photo documentation (standard 5 directions and ap with raised arms) * Filling out the BREAST-Q questionnaire \[11\]

Recorded data:

Age, weight, body mass, BMI, skin type typisation (normal, atypical, seborrheals, dehidrated, hyperhydrated (oedamatic)), preoperative cup size, presence of preoperative breast assymetry and its severity , past history, medication, smoking habits, oncological data, cTNM, pTN, pathological data, molecular genetic subtype, type of mastectomy (SM, SSM,ASM, NSM), type of primary reconstruction, neoadjuvant and adjuvant therapy, type of axillary treatment, , the size of used silicone implant(s).

Postoperative complications were classified following Clavien-Dindo Classification. \[12, 13\] Grade I complication does not require medication or surgical treatment (light inflammations, non-surgical haematoma or suffusion, seroma formation, partial skin/NAC loss, limited fat necrosis, SSI and lymphoedema). Grade II complication is a Grade I complication that requires medication or surgical interaction (antibiotic therapy, resuture due SSI and multiple puncture due chronic seroma). Grade III complication requires invasive surgical action (haematoma evacuation, chronic inflammation which requires reoperation, severe fat necrosis, full skin/ NAC necrosis and wound dehiscense). Grade IV complication means temporary organ failure. Grade V complication is one that leads to death.

The following data are collected in this trial: preoperative jugulum-nipple width, nipple-midline width, nipple-IMF width, vertical and horizontal width of the areola, Regnault Classification of the breast ptosis then repeating the above measurements during the follow-up (every 6 months) with parallel photo documentation and data recording of the BREAST-Q questionnaire and 5 point Likert-scale. \[14\]

Methods:

Enrolled patient who require unilateral SSM or SRNSM have undergone preoperative photo documentation, they filled out preoperative BREAST Q questionnaire and Re

• Complications rate [Срок оценки: five years of follow-up]