Comparison of the Cosmetic Results, Quality of Life and Patient Satisfaction Achieved With Round-block and Retroglandular Oncoplastic Breast Conserving Surgeries
Comparison of the Cosmetic Results, Quality of Life and Patient Satisfaction Achieved With Round-block and Retroglandular Oncoplastic Breast Conserving Surgeries
The aim of this clinical study is to analyze due long term follow-up, the clinical,
 oncological, aesthetic results and patients' reported quality of life and satisfaction in a
 responsive-adaptive (RAR) prospective, randomized study at a large number of patients whom
 receive round-block and retroglandular oncoplastic breast conserving surgeries.

 According to the study's hypothesis, breast conserving surgery can be oncologically
 successful and safe with low complication rates resulting in high rate of patient
 satisfaction and good quality of life, which can be maintained for a long time after WBI with
 the application of modern oncoplastic breast conserving surgeries. We assume in this study
 that against of the earliest and mostly studied round-block oncoplastic surgery, the
 retroglandular technique, firstly reported in the literature by the current authors, is also
 adequate for oncologically safe, radical tumor removal that comes with low complication
 rates, suited for adjuvant treatments and able to offer better cosmetic results (NAC does not
 distorted, and pathological scar will not develop) than round-block OPS and high rate of
 patient's satisfaction that can be maintained for long-term.
Introduction In the last four decades of oncological breast surgery, based on Umberto
 Veronesi and Bernard Fisher's prospective comparative studies, organ conservation became
 highly significant in the case of early breast cancer with the application of microscopically
 negative surgical margin and adjuvant whole breast irradiation (WBI), which is proven to
 offer the same survival chance as mastectomy.[1,2] However, in practice, the apparent
 benefits of organ conservation shaded by the need of second surgery, 5-30%, (repeated
 directed re-excision or mastectomy) due to microscopically positive surgical margins; the 3-5
 weeks long, logistically demanding radiotherapy; and the cosmetically impaired or distorted
 breasts that remains almost 30% of the surgeries. [3-5] The latter can be explained by our
 published previous prospective study that the patients report significantly intolerable
 cosmetic results after 10% volume loss from the inner quadrants and approximately 15-20%
 volume loss from the lateral quadrants, when its associates with adjuvant WBI. [6] Aside from
 volume reduction, during a traditional breast conserving surgery (BCS) the tumor bed is left
 behind as a cavity, whose posterior wall is composed of the pectoralis major muscle and the
 pectoral fascia, while its anterior wall is composed of skin. Already in the early
 postoperative stage, with the removal of the seroma, the skin retracts and adheres to the
 breast muscles or to the fascia. This process is accelerated by the irreversible of the
 complete residual parenchyma and the change of the skin's structure, elasticity and
 microcirculation during WBI. This could result 10-20% shrinkage of the breast. The breast
 shows a typical deformity with the directly curved incision line above the tumor as a result
 of secondary wound healing process mentioned above. Compared to the contralateral side its
 volume shrunk, the nipple dislocated to the axillary fold due to the adhesion of the
 upper-outer quadrant in case of this quadrant's volume loss and typical bird beak formation
 occurs in case of lower quadrants' border excision; while a central excision usually results
 in a so-called doughnut shaped breast with a central retractation. Additional challenge is
 the reconstruction of the post-BCS breast because it is more complicated and achieves poorer
 cosmetic results than the post-mastectomy breast construction. [7] In order to prevent the
 above listed disadvantages of BCS, a sophisticated organ conservation breast-surgery was
 developed with the adaptation of plastic surgery techniques in the last decade, which was
 named Oncoplastic Surgery (OPS) by Werner Audretsch. [8] These surgeries are volume reducing
 breast lift surgeries or their alterations, which are based on the knowledge of breast
 anatomy - especially on its blood circulation (e.g. Würinger's Septum), and its structural
 and aesthetic subunits (e.g. inframammary fold (IMF), nipple and areola complex (NAC)). The
 surgeries require particular plastic surgery knowledge. The OPS based on volume displacement
 using and mobilizing the glandular pillars to fill the wound cavity using the advantages of
 breast ptosis, narrowing the overall base diameter and the "footprint", and repositioning the
 NAC, which left behind after the radical removal of the tumor. The OPS is suitable to perform
 real quadrantectomy, even with a better aesthetic result then it is preoperatively. According
 to each segments of the breast, various oncoplastic techniques can be applied, giving the
 oncoplastic surgeon an unprecedented freedom to offer a personalized solution. The OPSs can
 be classified based on their technical complexity or on the level of volume (<20% / 20-50%)
 needed to be replaced (Level I./II.). [9] Following the OPS, the remaining scars caused by
 radiation become almost invisible, and due to the lack of wound cavity, adhesion does not
 occur.

 The most popular Level I. oncoplastic techniques are the periareolar or round-block
 techniques, or retroglandular technique, which was first published in the international
 literature by the current authors. These techniques are for those malignant tumors (cT< 3cm)
 which could be possibly located centrally in every quadrant and requires wide surgical
 excision less than 20% of the entire breast. [10, 11] The literature relied on oncoplastic
 breast conserving techniques is usually limited to retrospective cohort studies, while its
 prospective randomized comparison with traditional breast conserving surgery cannot be
 performed due to ethical reasons.

 The purpose of the current clinical study is to scientifically analyze and compare the
 clinical, oncological and aesthetic results of the standardized oncoplastic breast conserving
 surgical techniques, round-block versus retroglandular, in one center for unilateral,
 solitary, malignant breast tumors in a responsive-adaptive (RAR) prospective randomized trial
 with long term follow-up.

 Aim of the study The aim of this clinical study is to analyze due long term follow-up, the
 clinical, oncological, aesthetic results and patients' reported quality of life and
 satisfaction in a responsive-adaptive (RAR) [12] prospective, randomized study at a large
 number of patients whom receive round-block and retroglandular oncoplastic breast conserving
 surgeries.

 According to the study's hypothesis, breast conserving surgery can be oncologically
 successful and safe with low complication rates resulting in high rate of patient
 satisfaction and good quality of life, which can be maintained for a long time after WBI with
 the application of modern oncoplastic breast conserving surgeries. We assume in this study
 that against of the earliest and mostly studied round-block oncoplastic surgery, the
 retroglandular technique, firstly reported in the literature by the current authors, is also
 adequate for oncologically safe, radical tumor removal that comes with low complication
 rates, suited for adjuvant treatments and able to offer better cosmetic results (NAC does not
 distorted, and pathological scar will not develop) than round-block OPS and high rate of
 patient's satisfaction that can be maintained for long-term.

 Patients and method The participation in this study is voluntary. In this current
 response-adaptive (RAR) prospective randomized study the applied surgical operations count as
 routine interventions in the literature, as much as in our Department, with standardized
 techniques. The applicable round-block and retroglandular oncoplastic breast conserving
 surgeries do not mean new surgical procedures for the patients, not in their techniques, nor
 in their indications; the prospective examination serves only as a guarantee for the
 quantitative and qualitative data collection. The examination does not influence the applied
 oncological therapies; those are still executed based on the institution's preoperative and
 postoperative multidisciplinary breast oncological committee's professional decisions.

 The study does not change the complex oncological treatment in any ways, considering the NCI
 protocol.

 In this study the response-adaptive classification means that the choice of the optimal
 surgical procedure for the patient is not influenced by the clinical study. The decision
 making model is the same as it is in our department, same as for patients that are not
 participating in the study, so the subgroups chosen according to the oncological morbidity,
 the location of the tumor (the round-block technique is more appropriate for those ones that
 are closer to the surface, while the ones located more deeper, closer to the pectoralis major
 muscle are adequate for the retroglandular procedure), the breast size, the structure and
 ptosis of parenchyma. The applied and studied surgical techniques like aside of the clinical
 examination, do not require symmetrization.

 The current study does not include intervention in a scientific term due to the above listed
 reasons, so it is not differs of the routinely used treatment protocol.

 The primary endpoint of the study Correlation analysis of oncological control, cosmetic
 result, patients' satisfaction and quality of life achieved by various surgical techniques;
 and these follow-ups in one, two, three, four, and five years.

 The study's secondary endpoints To determine the complication's ratio of early and late
 surgeries, and the surgical strain (the length of the surgery and hospitalization).

 Based on the results, once it gains scientific confirmation, the retroglandular, oncoplastic
 breast conserving technique, proposed by the authors for the first time, could become a Level
 I oncoplastic technique.

 Patients:

 - Under the age of 65, suffering from unilateral (cT< 3cm) in situ or invasive breast cancer,
 who are fit for breast conserving surgeries, who had no previous breast surgery, independent
 from axillary surgery (sentinel lymph node biopsy or axillary block dissection)

 Excluding factors:

 -  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 a tumor

 -  Malignant invasive tumor in the past history (except for non-melanoma skin tumors)

 -  Mastectomy performed due to positive resection margin

 -  Prior breast surgery (e.g. aesthetic surgery, breast lift) 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

 -  Tumor requiring mastectomy, or clinically larger than 3 cm tumor primary, or mastitis
 carcinomatosa, lymphangitis carcinomatosa

 -  Long-term steroid usage, which changed the skin's quality and structure

 -  Patient under foster care, or psychically non-cooperative patient

 Preoperative examinations:

 -  Physical examination

 -  Triplet examination of the breast

 -  Preoperative core biopsy or FNAB

 -  Staging examinations: chest x-ray, abdominal ultrasound, bone scintigraphy

 -  Axillary ultrasound and cytological examination if required

 -  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

 -  Measurements of the areola's horizontal and vertical diameter

 -  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) [13]

 -  Filling out the BREAST-Q questionnaire [14]

 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.

 Postoperative complications were classified following Clavien-Dindo Classification[15, 16]
 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.[17]

 Methods Enrolled patients who require round-block, or retroglandular oncoplastic breast
 conserving surgery on one side, they filled out BREAST Q questionnaire and have undergone
 preoperative photo documentation, BCCT.core software analysis and breast ptosis detection
 according to Regnault Classification. In case of neoadjuvant therapy, the procedure is the
 same and the patient selection and data recording are performed preoperatively.

 Flow chart

 OPS, oncoplastic breast conserving surgery The patients after breast conserving surgery
 receive adjuvant therapy based on the decision of the multidisciplinary breast cancer board
 of the Institute. 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 then in the 3rd postoperative month
 then after every 6 months. The oncological follow-up carried out by the guideline of the
 Institute, and the follow-up lasts until the end of the 5th year. During this period,
 correction of the breast is not allowed.

 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
 round block oncoplastic breast conserving surgery, or the standardized retroglandular
 oncoplastic technique, which was first described in the literature by our workgroup. (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., 10.4. Periareolar oncoplastic
 technique; 10.13. Retroglandular oncoplastic breast-conserving surgical technique) [18]

 The round block oncoplastic breast conserving technique The surgical procedure planned after
 the exact localization of the cancer in surgical position. In case of non-palpable tumors,
 the preoperative markings are obligatory (isotope). Considering the previously mentioned
 facts, we mark in standing position the double round-lines and midline, the footprint and the
 line between the medioclavicular point and nipple, and its distal extension through the IMF.
 After desinfection and isolation, we de-epithelize the gap between the double round-lines,
 and we dissect the dermis from the best localization where we can reach the tumor. We suggest
 to infiltrate the wound line with adrenaline diluted saline (1:1000) before the incision to
 avoid the continuous bleeding of the subdermal plexus, which can disturb the procedure. If
 the tumor located close to the skin then we are not performing de-epithelization, we excise
 it with the skin. We mark every wall of the tumor bed with clips. After oncologically safe
 resection (resection border, tumor bed marking, intraoperative specimen
 mammography/ultrasound and control of the pathological "safe border" macroscopically), we
 dissect the surrounding parenchyma- so called parenchyma pillars- from the pectoral fascia
 and the skin, and we mobilize it. The line under the skin means, the layer under the
 subcutis, above the superficial fascia, so gives appropriate blood supply to the skin. The
 mobilization of the parenchyma pillars should be done adequately with absorbable sutures to
 avoid dead space, skin intrusion and breast deformity. After this the incision line should be
 placed 5 mm from the outer round line, so a dermis pillar should be left, and the skin is
 dissected from the parenchyma as needed. The outer round line should be tightened with a
 non-absorbable running Benelli suture to fit the areola then interrupted sutures placed to
 make tensionless the running intracutaneous suture. A subcutaneous drain should be left if
 needed until the 2nd postoperative day. We use a slight compression bandage for 12 hours. The
 wound should be covered according to the general surgical rules, if possible, using
 Steri-strip (topical mupirocin cream suggested on it), the sutures removed after 2-3 weeks.

 The retroglandular oncoplastic breast conserving technique We mark the midline and the
 breast's footprint in standing position. After desinfection and isolation in the OR, we
 infiltrate the subdermal plexus with the above mentioned way then we incise the skin slightly
 lateral in the IMF, around 7 cm long. We dissect with electrocauther the parenchyma with the
 pectoral fascia from the pectoralis major muscle at least until the mamilla. If the tumor's
 localization requires until the whole footprint is reached. We incise the fascia along with
 the parenchyma which contains the tumor and macroscopically 10 mm safe zone. If the tumor is
 palpable, we turn the parenchyma slightly inside-out, if not, we localize it at the maximum
 measurement detected according to the ROLL labeling. We mark the specimen and then send it to
 pathological examination, if needed intraoperative mammography and/or hystological
 examination. After marking the tumor bed, we directly adapt the surrounding parenchyma
 pillars with absorbable sutures, or inverting sutures, or if it requires, we adapt the tumor
 bed with so-called dual plane mobilization. The sentinel lymph node biopsy is performed from
 the same incision, while in case of axillary dissection, we perform it in a separate ca. 6 cm
 long incision line placed in the axillary fold. After revision, we close the fascia with
 absorbable running suture over the Redon drain then subcutaneous running suture with
 absorbable suture and finally intracutaneous skin closure. The Redon planned to be removed 50
 ml/day.

 The surgery required localization technique of the Institute, in case of non-palpable cancer,
 is the routinely used ultrasound guided or stereotaxic isotope labeling technique (ROLL),
 which marker is the same as the radiolabeled 99Tc albumin solution in sentinel lymph node
 biopsy.

 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)[18]

 Using and collecting cosmetic results The following data collected in standing position
 marking the midline and the IMF preoperatively then postoperatively in the 4th-6th week then
 in the 3rd postoperative month then after every 6 months: jugulum-nipple width,
 nipple-midline width, horizontal and vertical width of the areola 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, we
 give a score in a 1-100 scale measuring the variables of "satisfaction with the breast",
 "discomfort by radiotherapy", "psychosexual wellbeing" and "physical wellbeing". We use
 preoperatively a preoperative questionnaire and postoperatively a postoperative
 questionnaire. Higher rates show better quality of life. [14] The questionnaires are filled
 before the procedure and after the surgery 4th-6th weeks then postoperatively in the 3rd
 months and every 6th months.

 We use the Likert scale (1. definitely not, 2: no, 3: abstain, 4: agree, 4: definitely agree)
 for evaluating the subjective aesthetic outcome based on the photo documentation
 (preoperative, postoperative 4-6th weeks, 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
 oncoplastic procedure 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.

 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.

 Planned number of patients The planned number of the patients(calculated patients number plus
 10%): 110x2=220+ 22 cases ∑242 cases should be included.

 Planned time of patient inclusion: 1 year. Planned follow-up time The planned follow-up time
 after reconstruction and symmetrization is 5 year. Interim analysis performed after 2 years
 median follow-up period. Final analysis is performed 5 years after closing the patient
 inclusion period.
Inclusion Criteria:

 -  - Under the age of 65, suffering from unilateral (cT< 3cm) in situ or invasive breast
 cancer, who are fit for breast conserving surgeries, who had no previous breast
 surgery, independent from axillary surgery (sentinel lymph node biopsy or axillary
 block dissection)

 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 a tumor

 -  Malignant invasive tumor in the past history (except for non-melanoma skin tumors)

 -  Mastectomy performed due to positive resection margin

 -  Prior breast surgery (e.g. aesthetic surgery, breast lift) 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

 -  Tumor requiring mastectomy, or clinically larger than 3 cm tumor primary, or mastitis
 carcinomatosa, lymphangitis carcinomatosa

 -  Long-term steroid usage, which changed the skin's quality and structure

 -  Patient under foster care, or psychically non-cooperative patient