Examining and Comparing the Temporal Changes and Results of Cosmetic, Quality of Life and Patient Satisfaction Achieved With Immediate and Delayed-immediate Implant-based Breast Reconstruction Procedures and Contralateral Symmetrization Techniques
Examining and Comparing the Temporal Changes and Results of Cosmetic, Quality of Life and Patient Satisfaction Achieved With Immediate and Delayed-immediate Implant-based Breast Reconstruction Procedures and Contralateral Symmetrization Techniques
This is a response-adaptive (RAR) 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 breast
 reconstructive surgery with silicone implant (following SSM, ASM or NSM mastectomy) and
 symmetrization (mastopexy and/or silicone implant and/or Ultrapro mesh sling technique) over
 time.

 According to the hypothesis of the study, the results of implant-based breast reconstruction
 and symmetrization following advanced postmastectomy techniques significantly decrease over
 time and later results limited patient satisfaction rate.

 This is mainly due to the fact that over time, the natural breast differs from the
 reconstructed breast with silicone implant. Because of the different biological properties
 (gravity results ptosis on breast with mastopexy, significant volume increasement of the
 breast with mastopexy due to endocrine therapy, gradually progressive capsular contracture on
 the tumorous side, nipple flattening, nipple tattoo fading etc.) the two sides change
 differently resulting in significant asymmetry and consequently could lead to decreased
 patient satisfaction.

 The high degree of asymmetry over time (which can be similar to the difference between the
 result of a simple mastectomy and natural breast (control group)), may indicates additional
 surgeries or usage of medical devices, putting a financial burden on the patient and the
 health system. On the other hand, the symmetry can be achieved with bilateral skin-sparing
 mastectomies and implant-based immediate or delayed-immediate reconstructions is clearly
 better and change less with time. The mastectomy of the contralateral disease-free side is
 considered as an unreasonable burden for moderate risk patients.

 The information such as the need for multiple surgeries, change in symmetry over time etc.,
 should be an important part of the professional decision-making mechanism and the surgeon
 should inform the patient during the primer surgery. Nowadays due to the lack of
 evidence-based knowledge, it is not part of the patient's information and surgical planning
 internationally. Planning breast units, attention, capacity and financial resources must also
 be provided to meet the long-term needs of patients who underwent postmastectomy breast
 reconstruction. Simple mastectomy with an external prosthesis can be an alternative for
 patients with intolerable degree of asymmetry or on the contrary, the results may justify the
 need for bilateral mastectomy and reconstruction even in the absence of high oncological risk
 and for purely symmetrical and cosmetic reasons.
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. Unlike in the US, in Europe it is not
 yet common to perform prophylactic breast surgery on the contralateral side among average
 risk patients with unilateral breast cancer.

 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.

 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. 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.

 The immediate or delayed-immediate implant-based reconstruction of the affected breast
 following skin-sparing mastectomy techniques requires almost in all cases symmetrization of
 the contralateral breast. Symmetrization surgery involves mastopexy, volume reduction or
 silicone implant augmentation, or furthermore skin-sparing mastectomy with an implant-based
 reconstruction corresponding to the tumorous side. Symmetrization can be performed in one
 step with the tumorous breast surgery or more often at a deferred time.

 Postmastectomy breast reconstruction surgeries are well-known as an effective rehabilitation
 procedures, with significant psycho-oncological benefits to patients with low complication
 rates and high patient satisfaction. Postmastectomy breast reconstructive surgery however
 require more sophisticated surgical techniques, special expertise, longer surgical time and
 significantly higher costs than simplex mastectomies.

 The cosmetic results and patient satisfaction achieved with the immediate postmastectomy
 reconstructive techniques with the use of symmetrisation, are widely studied, and high,
 mainly in the early postoperative period.

 However, the long-term results of the more and more popular and widespread usage of
 skin-sparing mastectomies, immediate reconstructions and symmetrization surgery and the
 related patient satisfaction rates have so far not or only barely been in the focus of
 clinical trials, so the available scientific data is severely limited. The long-term
 disease-free survival with multidisciplinary treatments in early stage breast cancer could
 raise up to 85% of patients, so knowing the long-term changes of patient satisfaction,
 cosmetic result and symmetry of stressful and expensive immediate or delayed-immediate
 postmastectomy breast reconstruction surgeries is top priority.

 Aim of the study

 This is a response-adaptive (RAR) 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 breast
 reconstructive surgery with silicone implant (following SSM, ASM or NSM mastectomy) and
 symmetrization (mastopexy and/or silicone implant and/or Ultrapro mesh sling technique) over
 time.

 According to the hypothesis of the study, the results of implant-based breast reconstruction
 and symmetrization following advanced postmastectomy techniques significantly decrease over
 time and later results limited patient satisfaction rate.

 This is mainly due to the fact that over time, the natural breast differs from the
 reconstructed breast with silicone implant. Because of the different biological properties
 (gravity results ptosis on breast with mastopexy, significant volume increasement of the
 breast with mastopexy due to endocrine therapy, gradually progressive capsular contracture on
 the tumorous side, nipple flattening, nipple tattoo fading etc.) the two sides change
 differently resulting in significant asymmetry and consequently could lead to decreased
 patient satisfaction.

 The high degree of asymmetry over time (which can be similar to the difference between the
 result of a simple mastectomy and natural breast (control group)), may indicates additional
 surgeries or usage of medical devices, putting a financial burden on the patient and the
 health system. On the other hand, the symmetry can be achieve with bilateral skin-sparing
 mastectomies and implant-based immediate or delayed-immediate reconstructions is clearly
 better and change less with time. The mastectomy of the contralateral disease-free side is
 considered as an unreasonable burden for moderate risk patients.

 The information such as the need for multiple surgeries, change in symmetry over time etc.,
 should be an important part of the professional decision-making mechanism and the surgeon
 should inform the patient during the primer surgery. Nowadays due to the lack of
 evidence-based knowledge, it is not part of the patient's information and surgical planning
 internationally. Planning breast units, attention, capacity and financial resources must also
 be provided to meet the long-term needs of patients who underwent postmastectomy breast
 reconstruction. Simple mastectomy with an external prosthesis can be an alternative for
 patients with intolerable degree of asymmetry or on the contrary, the results may justify the
 need for bilateral mastectomy and reconstruction even in the absence of high oncological risk
 and for purely symmetrical and cosmetic reasons.

 Patients and method Participation in the study is voluntary. In this response-adaptive (RAR)
 prospective randomized study, the used standardized surgical techniques are considered to be
 routine procedures in the literature and iat department as well. The oncological and
 reconstructive surgeries do not represent new surgical procedures for 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 is used for a long time, and
 made individually for the patient's oncological disease (eg. nipple removal), breast size and
 degree of ptosis (NSM vs. SSM), which is the same way as patients are treated out-of-study.
 The principles of selecting symmetrizational techniques are presented in the introduction. In
 addition, reinforcement with Ultrapro mesh is used during mastopexy when the degree of the
 breast ptosis is at least Grade 3 or size D according to Regnault's classification or the
 patient has significant pseudoptosis, so the fibrous system and the skin of the breast have a
 very loose structure.

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

 Preoperative examinations:

 -  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

 -  Regnault Classification of breasts' ptosis

 -  Photo documentation (standard 5 directions and ap with raised arms) and the application
 of the BCCT.core program (regarding data protection regulations)

 -  Filling out the BREAST-Q questionnaire

 Recorded data:

 Age, body mass, height, BMI, pre-/postoperative cup sizes, presence of preoperative breast
 assymetry and its severity (BCCT.core software data), past history, medication, smoking
 habits, oncological data, cTNM, pTN, pathological data, molecular genetic subtype,
 neoadjuvant and adjuvant therapy, type of axillary treatment, locoregional cancer recurrance,
 metastasis.

 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 (BCCT.core software data), 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, type of delayed reconstruction, type and time of symmetrisation according
 to primary surgery, type of the primer surgery, bra cup size after the reconstruction and
 symmetrisation then measuring it yearly, the size of used silicone implant(s).

 Postoperative complications were classified following Clavien-Dindo Classification.

 Grade I complication (light inflammations, non-surgical haematoma or suffusion, seroma
 formation, partial skin/NAC loss, limited fat necrosis, SSI and lymphoedema) does not require
 medication or surgical treatment. 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, using BCCT.core program and
 data recording of the BREAST-Q questionnaire and 5 point Likert-scale.

 Methods Enrolled patients who require unilateral SSM, ASM, NSM, or bilateral SSM, ASM, NSM
 with immediate- or delayed-immediate implant based reconstruction, or only unilateral SM due
 oncological reason, they filled out preoperative BREAST Q questionnaire and have undergone
 preoperative photo documentation, BCCT.core software analysis. In case of neoadjuvant
 therapy, the procedure is the same and the patient selection and data recording are performed
 preoperatively.

 The patients after oncological surgery receive adjuvant therapy based on the decision of the
 multidisciplinary breast cancer board of the Institute. As a second step of the
 reconstruction the expander-implant exchange and contralateral breast's symmetrization
 happens at least 6 months after the adjuvant radiotherapy, and at least 3 months after the
 adjuvant chemotherapy. This happens at the same time in case of bilateral skin sparing
 mastectomies.

 Data collection: measurements of the patients, the photo documentation, filling the BCCT.core
 software database and the postoperative quality of life BREAST Q questionnaire made
 postoperatively in the 4th-6th week. Nipple reconstruction performed until the postoperative
 12-16th weeks in case of SSM and ASM. During the follow-up the above mentioned measurments,
 photo documentation and quality of life questionnaire will be checked first in the 3rd
 postoperative month then after every 6 months. The follow-up lasts until the end of the 5th
 year. During this period, correction of the breast is not allowed. The BREAST-Q questionnaire
 will be checked in every 6 months and the body measurements and photo documentation happens
 yearly in the SM group until the end of the 5th postoperative year to evaluate the
 contralateral breast's ptosis.

 Surgical therapy The treatment of the patients examined in the study relied on the techniques
 of the Breast and Sarcoma Department of the National Cancer Institute including standardized
 SSM, ASM and NSM, and SM in the quality of life control group. (See the detailed description
 of these: Z Mátrai, G Gulyás, T Kovács, M Kásler Principles and practice of oncoplastic
 breast surgery. Medicina Kiadó Zrt, 2019. 8. fejezet: Tradicional breast surgery, 8.1.1.
 Surgical technique of simple mastectomy and classical breast-consevring surgery; 11. fejezet
 Postmastectomy breast reconstruction, 11.4. Immediate breast reconstruction, 11.6.
 Skin-sparing and areola-sparing mastectomy, 11.7. Nipple-sparing mastectomy).

 According to the valid protocol of the National Cancer Institute, the surgery of the axilla
 can be either sentinel lymph node biopsy or axillary lymphadenectomy/ axillary block
 dissection, if needed with radiotherapy of the axillary and supraclavicular region depending
 on the regional stage of the breast cancer. (see as well in Z Mátrai, G Gulyás, T Kovács, M
 Kásler Principles and practice of oncoplastic breast surgery. Medicina Kiadó Zrt, 2019. 8.
 fejezet: Tradicional breast surgery, 8.1.2. Axillary lymph nodee dissection; 9. Sentinel
 lymph node biopsy in breast cancer).

 See the detailed standardized techniques of immediate or delayed-immediate breast
 reconstruction below: Z Mátrai, G Gulyás, T Kovács, M Kásler Principles and practice of
 oncoplastic breast surgery. Medicina Kiadó Zrt, 2019. 11. fejezet Postmastectomy breast
 reconstruction, 11.4. Immediate breast reconstruction, 11.8. Subpectoral/subserratus implant
 based breast reconstruction).

 For the involved patients the principles of the symmetrization surgeries at Department is
 standardized. To achieve the best result of symmetrisation, to built a natural shape breast
 choosing an optimal implant size according to the footprint width, quality, quantity and the
 tension of the skin at the ipsilateral tumorous breast side and volume increasement with
 silicone implant augmentation in submuscular position and/or volume reduction and/or
 mastopexy at the contralateral side.

 According to the institutional practice the standardized inferior pedicle Wise technique for
 mastopexy from an invert-T incision is chosen. If there is an expressed taint for ptosis, in
 the subcutaneous layer an extra Ultrapro mesh sling is used (size of 7x15 cm) to suspened the
 breast. (See detailed surgical technique: Z Mátrai, G Gulyás, T Kovács, M Kásler Principles
 and practice of oncoplastic breast surgery. Medicina Kiadó Zrt, 2019. Chapter 12. Breast
 shape and volume symmetrisation surgeries, nipple and areola reconstruction, 12.2. The link
 between removal of the breast cancer and symmetrisation.) To compare the postoperative
 aesthetic result of SSM and ASM, the nipple reconstruction and the NAC tattooing is
 obligatory. The technique of the nipple reconstruction is standardized in enrolled patients.
 (See detailed surgical technique: Z Mátrai, G Gulyás, T Kovács, M Kásler Principles and
 practice of oncoplastic breast surgery. Medicina Kiadó Zrt, 2019. 12. fejezet Breast shape
 and volume symmetrisation surgeries, nipple and areola reconstruction, 12.4.3. Techniques for
 reconstructing the nipple.)

 Using and collecting cosmetic results The following data collected in standing position
 marking the midline and the IMF preoperatively then at the step of delayed reconstruction and
 at symmetrization: jugulum-nipple width, nipple-midline width and nipple-IMF width.

 The breast ptosis examination performed according to Regnault Classification at the beginning
 and after symmetrization.

 The primary aesthetic stage will be documented with standard photo documentation using valid
 BCCT.core software making it measurable which allows us to compare it. the photo
 documentation performed the standard way in 5 position (antero-posterior (ap), 45 degree
 oblique and 90 degree lateral), in ap direction both ways arms up and down with strict
 adherence to personal privacy policies. The patients are anonymous on the pictures without
 their faces, and the photo documentation performed without jewelry. The mentioned software
 counts measurements regarding to the photo documentation and gives a 4-point rating scale (1:
 excellent, 2: good, 3: acceptable, 4: non-acceptable). These numerical results can be
 statistically analyzed.

 The quality of life is measured by BREAST-Q validated questionnaire. According to this, a
 score is given in a 1-100 scale measuring the variables of "satisfaction with the breast",
 "discomfort by radiotherapy", "psychosexual wellbeing" and "physical
 wellbeing".Preoperatively a preoperative questionnaire and postoperatively a postoperative
 questionnaire is filled. Higher rates show better quality of life. The questionnaires are
 filled before the procedure and after the surgery in the 3rd months and every 6th months.

 Likert scale is used (1. definitely not, 2: no, 3: abstain, 4: agree, 4: definitely agree)
 for evaluating the subjective aesthetic outcome based on the photo documentation
 (preoperative, 4 weeks after delayed reconstruction with symmetrization, 3rd months, every 6
 months 5 years long). Based on the photo documentation three, non-involved breast surgeons
 make the evaluation separately without communication. The results are collected and averaged.

 Follow-up The follow-up is similar to the surgical and oncological follow-up in the National
 Cancer Institute, so it is not a burden for the patients The primary check-up and data
 registration performed preoperatively, the second check-up performed 4-6th weeks after the
 delayed reconstruction and symmetrization then 3rd postoperative months with photo
 documentation, body measurements, body mass calculation and BREAST-Q questionnaire.

 After this the photo documentation, body measurements, body mass calculation and BREAST-Q
 questionnaire examination performed every 6 months until the 5th year.

 In SM group the body measurements, photo documentation made in the 3rd months and
 measurements of the contralateral side and the BREAST-Q questionnaire performed every 12
 months.

 The bioethical background of the study It is a non-interventional clinical study is conducted
 by the competent regional research ethics committees in accordance with the Medical law 164 /
 A. § (2).

 This non-interventional clinical trial is performed with the permission of the Ethical
 Committee of the National Cancer Institute according to the 23/2002. (V.9.) Medical
 Regulation.

 The Researchers commit themselves to protect the patient's data, photo documentation in
 accordance with the WHO Good Clinical Practice ( based on the Helsinki Declaration) and the
 applicable provisions of the General Data Protection Regulation (GDPR) regarding the
 international ethical and scientific quality requirements pertaining to the design, conduct,
 documentation and reporting principles of tests conducted on humans.

 Data collection and registration It is performed with the registration sheet for computer
 processing and BREAST-Q questionnaire which is an internationally validated and authorized
 mirror translated questionnaire. Digital photo documentation (standard 5 direction with
 lowered arms and ap direction with raised arms) The BCCT.core made with at least 9 megapixel
 photo documentation, ap and lateral directions with lowered and raised arm to calculate
 numerically with a validated procedure the aesthetic outcome.
Inclusion Criteria:

 -  Under the age of 65 with uni- or bilateral primary breast cancer ( clinical Stage
 0-III), needing modern skin sparing mastectomy, nipple sparing mastectomy or areola
 sparing mastectomy independently of the axillary surgery, having immediate or
 delayed-immediate implant based reconstrucion on the ipsilateral side and
 symmetrisation on the contralateral side ( mastopexy and/or implant based
 reconstruction and/or breast sling with ultrapro mesh)

 -  Control group: patients under 65 years with unilateral simplex mastectomy without
 breast 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)

 -  Mastectomyand 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

 -  If breast correction performed during the 5 years follow up