Table of Contents 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144

Yara Blok

BREAST RECONSTRUCTIVE SURGERY Improving outcomes and patient satisfaction Yara Lynn Blok

BREAST RECONSTRUCTIVE SURGERY Improving outcomes and patient satisfaction Yara Lynn Blok

Publication of this thesis was financially supported by the Leiden University, Nederlandse Vereniging voor Plastische Chirurgie, Dijklander Ziekenhuis, Leiden University Medical Center Department of Surgery, ABN AMRO and Chipsoft Cover design: Yara Blok Provided by thesis specialist Ridderprint, ridderprint.nl Printing: Ridderprint Layout and design: Jeroen Reith, persoonlijkproefschrift.nl ISBN: 978-94-6506-388-1 Y.L. Blok, 2024, Amsterdam, the Netherlands All rights reserved. No parts of this publication may be reproduced in any form or by any means without permission of the author.

BREAST RECONSTRUCTIVE SURGERY improving outcomes and patient satisfaction Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Leiden, op gezag van rector magnificus prof.dr.ir. H. Bijl, volgens besluit van het college voor promoties te verdedigen op donderdag 31 oktober 2024 klokke 14:30 uur door Yara Lynn Blok Geboren te Muiderberg

PROMOTIECOMMISSIE Promotoren: Prof. Dr. J.A. van der Hage Prof. Dr. M.A.M. Mureau Erasmus MC, Universitair Medisch Centrum Rotterdam COPROMOTOR: Dr. N.M.A. Krekel Alrijne Ziekenhuis Promotiecommissie: Prof. Dr. M.J.W.M. Wouters Prof. Dr. E.M.A. Bleiker Prof. Dr. A.A. Piatkowski Maastricht Universitair Medisch Centrum Prof. Dr. M.T.F.D. Vrancken Peeters Antoni van Leeuwenhoek

TABLE OF CONTENTS Chapter 1 | General introduction and thesis outline 7 Part I Oncoplastic breast surgery 15 Chapter 2 | An analysis of complication rates and the influence on patient satisfaction and cosmetic outcomes following oncoplastic breast surgery 17 Journal of Plastic, Reconstructive & Aesthetic Surgery, 2022 Part II Pectoral fascia preservation in immediate breast reconstruction 33 Chapter 3 | Pectoral fascia preservation in oncological mastectomy to reduce complications and improve reconstructions: a systematic review 35 Plastic Reconstructive Surgery Global Open, 2021 Chapter 4 | Preservation of the pectoral fascia in mastectomy with immediate reconstruction, a nationwide survey 53 Journal of Surgical Research, 2023 Part III Implant loss risk in implant-based breast reconstruction 63 Chapter 5 | Implant loss and associated risk factors following implantbased breast reconstructions 65 Plastic Reconstructive Surgery Global Open, 2021 Chapter 6 | Nation-wide validation of a multicenter risk model for implant loss following implant-based breast reconstruction 81 Journal of Plastic, Reconstructive & Aesthetic Surgery, 2022 Chapter 7 | Risk prediction of implant loss following implant-based breast reconstruction: a population-based study using Dutch Breast Implant Registry (DBIR) data 95 Submitted Discussion and Conclusion 115 Chapter 8 | General discussion and future directions 117 Chapter 9 | English summary / Nederlandse samenvatting 129 Appendix | List of publications / Dankwoord / Curriculum vitae 137

1 General Introduction and Thesis Outline

8 Chapter 1 Breast Cancer Breast cancer is, with a ten-year prevalence of 120.000, the most common type of cancer among women in the Netherlands.1 Approximately 1 in 8 women will develop breast cancer at some point in their life. On average, 87% of the women with breast cancer survive at least 5 years and over 77% survives at least 10 years.2 Because of improvements in early diagnosis and more efficient therapies, breast cancer becomes more a chronic condition than a life-threatening illness.3 The treatment for breast cancer is very personalized and depends on tumor subtype, tumor stage, genomic tests, the presence of known mutations in inherited breast cancer genes and patient characteristics. For treating early-stage and locally advanced breast cancer, the general recommendation is breast surgery to remove the tumor, and (neo-) adjuvant treatment depending on the tumor characteristics, such as radiotherapy, chemotherapy, immunotherapy and/or hormonal therapy.4,5 Breast Cancer Surgery Cosmetic results after breast cancer surgery have become increasingly important, partly because of the current favorable life expectancy after breast cancer treatment. While breast cancer surgery has developed over the years, the goals have remained the same: complete removal of the tumor obtaining negative margins, with the least degree of breast deformity. In breast-conserving surgery, the tumor is removed with a safe cancer-free margin and most of the healthy breast tissue is preserved. An oncoplastic procedure may be necessary to obtain an aesthetically pleasant result. Breast-conserving surgery is mostly followed by adjuvant radiotherapy. The alternative is a mastectomy, in which all breast tissue is removed. The breast mound can be restored with an autologous or implantbased breast reconstruction, or a combination of these two procedures.6 In some cases, adjuvant radiotherapy is necessary following mastectomy to eliminate microscopic disease. Oncoplastic Breast Surgery Oncoplastic breast surgery (OPS), which involves plastic surgery techniques to reconstruct the breast after breast-conserving surgery, has gained popularity over the last decades. It optimizes oncological safety and cosmetic outcomes at the same time, combining wide resection margins with the best principles of plastic reconstructive surgery.6 Therefore, compared to conventional breast-conserving surgery, OPS may be associated with fewer conversions to mastectomy and lower re-excision rates.7 There are two different approaches for OPS, based on the location of the tumor, the volume of the excised tissue and the size and ptosis of the patient’s breast.8 The volume replacement technique fills up the defect after excision of the tumor with tissue adjacent to the breast. The volume displacement technique uses the remaining tissue of the breast to reconstruct the defect. Volume replacement techniques are islanded or pedicled chest wall

9 General Introduction and outline of this thesis fasciocutaneous perforator flaps, such as the thoracodorsal artery perforator (TDAP) flap and the anterior- or lateral intercostal artery perforator (AICAP or LICAP) flap. These techniques are indicated in patients with small breasts without ptosis. The most used volume displacement technique is the Wise pattern mammoplasty with a variation in nipple areola complex pedicles. For this technique, a larger breast with some degree of ptosis is required.9-11 Mastectomy Despite the rise in the use of breast-conserving surgery, mastectomy remains indicated in a substantial part of patients with breast cancer. In 2020 in the Netherlands, 1372 patients with ductal carcinoma in situ (DCIS) underwent surgery, 67% underwent breast-conserving surgery and 31% a mastectomy. For invasive breast cancer, 10.574 patients underwent breast surgery of whom 65.2% underwent breast-conserving surgery and 34.5% received a mastectomy.12 In addition, the rates of contralateral and bilateral risk reducing mastectomy procedures have increased substantially.13, 14 Therefore, studies focusing on improving outcomes of mastectomy remain important. Over the past decades, less invasive oncological breast surgery has become increasingly popular. Halsted’s radical mastectomy, which completely removed the pectoralis major muscle (PM), was replaced by the simple mastectomy, in which the PM was spared and only the pectoral fascia (PF) was removed, with better biomechanical outcomes and fewer postoperative pain.15-17 The development of skin and nipple-sparing mastectomies and the rise of breast-conserving surgery as an oncologically safe alternative to mastectomy, are the result of a greater focus on long-term outcomes.17 The majority of those changes are the result of the awareness that more extensive surgery does not always lead to better oncological outcomes and may even harm long-term aesthetic outcomes and quality of life (QoL). In addition to the realization that more extensive surgery does not always lead to better outcomes, the following question arises: ‘is it still necessary to remove the PF during a mastectomy?’ Presently, it is common practice to routinely remove the PF during a (skin-sparing) mastectomy to guarantee tumor-free margins. However, the need for this is debatable. The PF is part of the muscular anatomy, instead of the breast glandular tissue. Therefore, other than in extremely rare cases of tumor growth into the PF, the oncological benefit of PF resection seems questionable.18 In fact, PF preservation may enhance breast reconstructive outcomes and postoperative results. It might reduce seroma formation due to its function in lymph drainage. Furthermore, postoperative bleeding and pain may be decreased by avoiding surgical injury to the PM. In addition, the PF, which is a strong fibro-elastic layer, might improve breast implant coverage.19, 20 Although the potential advantages of PF preservation seem evident, literature on this topic 1

10 Chapter 1 is scarce and opinions and surgical techniques differ between surgeons, medical centers and countries. Implant-Based Reconstruction Implant-based reconstruction is the most common technique for reconstructing the breast following a mastectomy.21 It can be performed in two stages or in one stage (direct-to-implant (DTI)). Generally, the reconstruction is performed in two stages. First, a tissue expander (TE) is placed subpectorally at the time of mastectomy, which is replaced by a definitive implant during a second surgery. The alternative is a DTI approach, where the definitive implant is placed immediately, and no second procedure is indicated. However, with DTI reconstructions, it is more challenging to obtain symmetry and complication rates (including infection, skin necrosis, and implant exposure) may be higher, compared to two-stage procedures.22 Although implant-based reconstruction generally leads to a less natural result compared with an autologous reconstruction, the advantages of implant-based breast reconstructions are the simplicity, safety, and costeffectiveness without potential donor-site morbidity. Furthermore, the operative time is shorter, the overall recovery is quicker and there is a shorter length of hospital stay.23, 24 Among all possible complications, such as surgical site infections (SSI), skin flap necrosis, nipple necrosis, seroma, and hematoma,25 implant loss is the most serious complication, which is observed after 1.8%-16.9% of all implant-based breast reconstructions. It significantly affects the patient’s life in both a physical and emotional manner. Re-operations related to implant loss may cause an important decrease in patient satisfaction and a substantial increase in hospital expenses. It might also postpone the start of additional adjuvant therapy.26-31 Several risk factors for implant loss have been identified in the literature over time, such as advanced age, obesity, smoking status, and DTI reconstruction.27 However, a risk assessment model to improve patient information and decisionmaking regarding the most appropriate type of mastectomy and reconstruction has not been developed yet and would be of great value for better preoperative counseling. Aim and Thesis Outline This thesis aimed to improve patient satisfaction and the postoperative outcomes after reconstructive surgery following breast cancer. Part I of the thesis addresses oncoplastic breast surgery and aimed to analyze whether patients are satisfied after oncoplastic breast surgery and whether there are differences between the two techniques in postoperative outcomes and patient satisfaction. Studies in part II investigated the evolution of mastectomy techniques and focus on pectoral fascia preservation. This part aimed to provide an answer to the following questions: is pectoral fascia preservation oncologically safe, does it improve

11 General Introduction and outline of this thesis postoperative outcomes and do surgeons actually use this technique in the Dutch practice? Part III contains studies concerning implant-based breast reconstruction and aimed to create a validated risk prediction model for implant loss. Part I – Oncoplastic breast surgery In chapter 2, oncoplastic breast surgery and the postoperative outcomes are discussed. The study focuses on complications, patient satisfaction and cosmetic outcomes. Furthermore, the outcomes of the two different techniques, volume replacement and volume displacement, were analyzed and compared. Part II – Pectoral fascia preservation in immediate breast reconstruction Pectoral fascia removal during a mastectomy is still common practice in the Netherlands. Chapter 3 provides an overview of literature concerning pectoral fascia preservation during a mastectomy, with the main outcomes oncological safety, complication rates, implant loss and cosmetic outcomes. In addition to this topic, chapter 4 reports on a nation-wide survey on the opinions of Dutch plastic surgeons and breast surgeons regarding pectoral fascia preservation. Part III – Implant loss in implant-based breast reconstruction Implant loss is the most feared complication following implant-based reconstructions. Therefore, significant risk factors for implant loss following implant-based reconstructions were identified in chapter 5 and a multi-center risk model for implant loss was created. The study in chapter 6 aimed to validate the risk model for implant loss, which was developed in the previous chapter using data from the Dutch Breast Implant Registry (DBIR). The study in chapter 7 aimed to create a validated risk prediction model for implant loss with DBIR data which would be very useful in decision-making and preoperative counseling for women who consider implant-based reconstruction. Finally, in chapter 8, the main findings and conclusion of this thesis are discussed and suggestions for future research are provided. 1

12 Chapter 1 REFERENCES 1. Integraal kankercentrum Nederland, IKNL. Prevalentie borstkanker. Available from: https://iknl.nl/kankersoorten/borstkanker/registratie/prevalentie. [cited 24 june 2024] 2. Breast cancer in the Netherlands. National Institute for Public Health and Environment. Available from: https://www.rivm.nl/en/breast-cancer-screening-programme/breastcancer-in-netherlands. [cited 21 may 2023] 3. Bodai BI, Tuso P. Breast cancer survivorship: a comprehensive review of long-term medical issues and lifestyle recommendations. Perm J 2015; 19(2):48-79. 4. Federatie Medisch Specialisten, richtiljnen, borstkanker. Available from: https:// richtlijnendatabase.nl/richtlijn/borstkanker/startpagina_-_borstkanker.html [cited 24 june 2024] 5. Breast Cancer - Types of Treatment. Available from: https://www.cancer.net/cancertypes/breast-cancer/types-treatment [cited 21 may 2023]. 6. Kaufman CS. Increasing Role of Oncoplastic Surgery for Breast Cancer. Curr Oncol Rep 2019; 21(12):111. 7. Heeg E, Jensen MB, Hölmich LR, et al. Rates of re-excision and conversion to mastectomy after breast-conserving surgery with or without oncoplastic surgery: a nationwide population-based study. Br J Surg 2020; 107(13):1762-1772. 8. Yang JD, Lee JW, Kim WW, et al. Oncoplastic surgical techniques for personalized breast conserving surgery in breast cancer patient with small to moderate sized breast. J Breast Cancer 2011; 14(4):253-61. 9. Hakakian CS, Lockhart RA, Kulber DA, Aronowitz JA. Lateral Intercostal Artery Perforator Flap in Breast Reconstruction: A Simplified Pedicle Permits an Expanded Role. Ann Plast Surg 2016; 76 Suppl 3:S184-90. 10. Hamdi M, Van Landuyt K, Hijjawi JB, et al. Surgical technique in pedicled thoracodorsal artery perforator flaps: a clinical experience with 99 patients. Plast Reconstr Surg 2008; 121(5):1632-1641. 11. Noguchi M, Yokoi-Noguchi M, Ohno Y, et al. Oncoplastic breast conserving surgery: Volume replacement vs. volume displacement. Eur J Surg Oncol 2016; 42(7):926-34. 12. Nabon Breast Cancer Audit (NBCA) jaarverslag uitkomsten 2020 (annual report 2020), https://dica.nl/media/2678/NBCA%20jaarverslag%202020_oktober_pdf.pdf [cited 25 may 2023]. 13. Albornoz CR, Bach PB, Mehrara BJ, et al. A paradigm shift in U.S. Breast reconstruction: increasing implant rates. Plast Reconstr Surg 2013; 131(1):15-23. 14. Cemal Y, Albornoz CR, Disa JJ, et al. A paradigm shift in U.S. breast reconstruction: Part 2. The influence of changing mastectomy patterns on reconstructive rate and method. Plast Reconstr Surg 2013; 131(3):320e-326e. 15. Halsted WS. I. The Results of Operations for the Cure of Cancer of the Breast Performed at the Johns Hopkins Hospital from June, 1889, to January, 1894. Ann Surg 1894; 20(5):497555. 16. Patey DH, Dyson WH. The prognosis of carcinoma of the breast in relation to the type of operation performed. Br J Cancer 1948; 2(1):7-13. 17. Zurrida S, Bassi F, Arnone P, et al. The Changing Face of Mastectomy (from Mutilation to Aid to Breast Reconstruction). Int J Surg Oncol 2011; 2011:980158. 18. Vallejo da Silva A, Rodriguez FR, Loures CM, Lopes VG. Mastectomy in the era of implant-based reconstruction: should we be removing the pectoralis fascia? Breast 2012; 21(6):779-80. 19. Abdelhamid M, Alkilany M, Lotfy M. Pectoral fascia preservation during modified radical mastectomy: why and when. The Egyptian Journal of Surgery 2017; 36(4):333-335.

13 General Introduction and outline of this thesis 20. Stecco A, Masiero S, Macchi V, et al. The pectoral fascia: anatomical and histological study. J Bodyw Mov Ther 2009; 13(3):255-61. 21. Bertozzi N, Pesce M, Santi P, Raposio E. Tissue expansion for breast reconstruction: Methods and techniques. Ann Med Surg (Lond) 2017; 21:34-44. 22. Mesbahi AN, McCarthy CM, Disa JJ. Breast reconstruction with prosthetic implants. Cancer J 2008; 14(4):230-5. 23. Colwell AS, Taylor EM. Recent Advances in Implant-Based Breast Reconstruction. Plast Reconstr Surg 2020; 145(2):421e-432e. 24. Sinha I, Pusic AL, Wilkins EG, et al. Late Surgical-Site Infection in Immediate ImplantBased Breast Reconstruction. Plast Reconstr Surg 2017; 139(1):20-28. 25. Poppler LH, Mundschenk MB, Linkugel A, et al. Tissue Expander Complications Do Not Preclude a Second Successful Implant-Based Breast Reconstruction. Plast Reconstr Surg 2019; 143(1):24-34. 26. Darragh L, Robb A, Hardie CM, et al. Reducing implant loss rates in immediate breast reconstructions. Breast 2017; 31:208-213. 27. Fischer JP, Wes AM, Tuggle CT, 3rd, et al. Risk analysis of early implant loss after immediate breast reconstruction: a review of 14,585 patients. J Am Coll Surg 2013; 217(6):983-90. 28. Knight HJ, Musgrove JJ, Youssef MMG, et al. Significantly reducing implant loss rates in immediate implant-based breast reconstruction: A protocol and completed audit of quality assurance. J Plast Reconstr Aesthet Surg 2020; 73(6):1043-1049. 29. Kouwenberg CAE, van Hoogdalem LE, Mureau MAM, et al. Patients’ and surgeons’ experiences after failed breast reconstruction: A qualitative study. J Plast Reconstr Aesthet Surg 2021; 74(7):1480-1485. 30. Ozturk CN, Ozturk C, Soucise A, et al. Expander/Implant Removal After Breast Reconstruction: Analysis of Risk Factors and Timeline. Aesthetic Plast Surg 2018; 42(1):64-72. 31. Sue GR, Sun BJ, Lee GK. Complications After Two-Stage Expander Implant Breast Reconstruction Requiring Reoperation: A Critical Analysis of Outcomes. Ann Plast Surg 2018; 80(5S Suppl 5):S292-s294. 1

I Oncoplastic breast surgery PART

2 An analysis of complication rates and the influence on patient satisfaction and cosmetic outcomes following oncoplastic breast surgery Y.L. Blok P.S. Verduijn L.U.M. Corion J.M. Visser C.C. van der Pol J.A. van der Hage M.A.M. Mureau N.M.A. Krekel Journal of Plastic, Reconstructive & Aesthetic Surgery, 2022

18 Chapter 2 ABSTRACT Introduction: This study aimed to evaluate complication rates, patient satisfaction and cosmetic outcomes after oncoplastic breast-conserving surgery. Furthermore, outcome differences between volume displacement and volume replacement techniques and the effect of postoperative complications on outcomes were evaluated. Methods: This was a prospective single-center study addressing patients who underwent oncoplastic breast-conserving surgery from 2017 to 2020. The BREAST-Q was used to measure patient satisfaction and cosmetic outcomes were assessed by patient self-evaluation and panel evaluation based on medical photographs. Results: A total of 75 patients were included. The overall complication rate was 18.7%, of which 4% required invasive interventions. Median BREAST-Q scores ranged from 56 to 100 and cosmetic outcomes were scored good to excellent in 60-86%. No differences in complications were observed between volume replacement and volume displacement techniques. Following volume displacement techniques, patients reported higher BREAST-Q scores for the domain ‘physical well-being of the chest’ and lower cosmetic outcomes scores for ‘mammary symmetry’. Patients with complications scored significantly lower on several domains of the BREAST-Q and in various cosmetic outcome categories. Conclusion: In this cohort, an overall complication rate of 18.7% was observed. Patients were generally satisfied and most cosmetic outcomes were good to excellent. Volume displacement or replacement techniques were performed for different indications and generally showed comparable results. Expected differences in physical discomfort and symmetry between both techniques were observed. In addition, the occurrence of complications resulted in lower patient satisfaction and cosmetic outcomes. These findings emphasize the importance of thorough preoperative counselling.

19 Outcomes following oncoplastic breast surgery INTRODUCTION While breast cancer surgery has evolved over the years, the goals have remained the same: complete removal of the tumor acquiring negative margins, with the least degree of breast deformity. The cosmetic results after breast cancer surgery have become increasingly important, partly because of the current favorable life expectancy after breast cancer treatment.1 Therefore, oncoplastic breastconserving surgery (OPS) has rapidly gained popularity over the last decade. It optimizes oncological safety and cosmetic outcomes, combining the best principles of surgical oncology with the possibility of larger resection margins with plastic reconstructive surgery.2 As a result, OPS might be associated with less conversions to mastectomy and lower re-excision rates compared to breast-conserving surgery alone.3 In addition, breast-conserving surgery plus radiotherapy might even result in an improved survival compared to mastectomy in early breast cancer.4 By combining OPS with neoadjuvant chemotherapy, leading to preoperative tumor reduction, more patients are eligible for this technique. This implies that OPS can be a cosmetically acceptable alternative to breastconserving surgery or mastectomy without compromising local oncological safety, even in tumors that are relatively large compared to the breast size.5, 6 OPS can be categorized in two different approaches, based on tumor location and excised volume, in combination with the volume and ptosis of the patient’s breast.7 Volume replacement is a technique using tissue adjacent to the breast, to fill up the gap that is left behind after tumor removal. Volume displacement is a technique that uses the remaining breast tissue to fill up the defect.8 Volume replacement techniques are required in patients with small and non-ptotic breasts. Most suitable techniques are islanded or pedicled chest wall fasciocutaneous perforator flaps like the lateral or anterior intercostal artery perforator flap (LICAP or AICAP)9 or the thoracodorsal artery perforator (TDAP) flap.10 For volume displacement, only possible in patients with some degree of ptosis, the Wise pattern mammoplasty using different nipple areola complex pedicles is the most common approach.11 The objectives of this study were to assess complication rates, patient satisfaction and cosmetic outcomes after OPS, investigate the influence of complications on patient satisfaction and cosmetic outcomes, and compare these results between volume replacement and volume displacement techniques. 2

20 Chapter 2 METHODS Study design This study was designed as a prospective single center study, including all patients who underwent OPS (volume replacement or volume displacement) for breast cancer between January 2017 and December 2020 at the Alrijne Hospital in the Netherlands. Ethical considerations The study protocol was approved by the local institutional ethical review board (N21.053) and informed consent was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki and reported according to the strengthening the reporting of observational studies in epidemiology (STROBE) statement.12, 13 Surgical technique All patients were operated by four plastic surgeons. For volume displacement, the Wise or Grisotti technique was used.11, 14 For volume replacement, the TDAP flap or bilobed swing flap was used.10 15 Complications and definitions All complications were collected in a prospective manner. Postoperative complications (seroma, hematoma, surgical site infection (SSI), wound dehiscence and necrosis) were graded according to Clavien-Dindo classification (CD).16 In this study, for grade 1 complications, the normal postoperative course was not deviated and no interventions were necessary. Grade 2 complications required pharmacological treatment with antibiotics. Grade 3 complications required surgical drainage. Clinically relevant postoperative complications were defined as complications with a CD score of 2 or more. BREAST-Q Patient reported quality of life and satisfaction was measured with the BREAST-Q breast conserving therapy (BCT) module, which was sent online to all participating patients (Castor EDC). The BREAST-Q is a validated, disease-specific patient reported outcome measure and patient reported experience measure to assess patient satisfaction and health-related quality of life.17 Responses from each scale were summed and transformed into Q-scores ranging from 0 to 100, with higher numbers representing greater satisfaction or quality of life. Patient reported cosmetic outcomes Patients received an online questionnaire for self-assessment of cosmetic outcomes. Participants were asked to provide a score, from 1-4 (1: poor, 2: fair, 3:

21 Outcomes following oncoplastic breast surgery good, 4: excellent), for each of the following four categories: mammary symmetry, scarring, areola-nipple symmetry and global judgment. The score and cosmetic categories were derived from previous research.18 In case the patient underwent a contralateral symmetrization, patients were asked to fill in these questions according to the situation before the symmetrizing surgery. Patients in whom the nipple was excised, the nipple areolar symmetry was not scored. Panel reported cosmetic outcomes In accordance with the standard postoperative protocol after breast reconstruction, five-point view medical photographs were made at a minimum of three months after the surgery and uploaded in the patient files. In case these photographs were not present in the patient files, patients were invited for an appointment with the medical photographer. Based on these photographs, cosmetic outcomes were evaluated by a panel consisting of two independent plastic surgeons and two laymen. The members of the panel scored cosmetic outcomes independently and were blinded for any clinical information. All members of the panel were invited to evaluate the breasts in the previously mentioned four categories with a score from 1-4. Patients who underwent a contralateral symmetrization without available photographs before this procedure, were excluded from the analysis. The nipple areolar symmetry was not scored if the nipple was excised during OPS. Statistical analysis Continuous variables are presented as median values with interquartile ranges (IQRs) and frequency percentages were calculated for categorical variables. Differences in baseline characteristics between groups were tested with MannWhitney U tests, chi-square tests or Fisher’s exact tests. Comparisons between volume displacement and volume replacement techniques were performed using the chi-square test for postoperative complications and Mann-Whitney U test for BREAST-Q and cosmetic outcomes. The same tests were performed for comparisons between patients with and without complications. Patients with missing data on (domains of) the BREAST-Q or cosmetic outcomes were excluded from this specific part of the analysis. The level of inter-observer agreement between the two laymen and the two specialists was derived from Cohen’s kappa values and defined as follows: 0-0.20 slight agreement, 0.21-0.40 fair agreement, 0,41-0.60 moderate agreement, 0.61-0.80 substantial agreement and 0.81-1 excellent agreement. A two-sided P-value of <0.05 was considered statistically significant. IBM SPSS statistics (version 26) was used for standard statistical analysis. 2

22 Chapter 2 RESULTS Patient selection Between January 2017 and December 2020, a total of 75 patients underwent OPS. Five patients were lost to follow-up and the remaining 70 patients were invited to participate in the BREAST-Q, self-assessment of cosmetic outcomes and panel evaluation of cosmetic outcomes. The BREAST-Q was completed by 52 patients (response rate 74.3%), self-assessment of cosmetic outcomes by 50 patients (response rate 71.4%) and panel evaluation was performed in 40 patients (57.1%). Study population The total study population consisted of 75 women with a median age of 61 years (IQR: 52-67 years) and a median BMI of 27 kg/m2 (IQR: 24.0-30.1 kg/m2). Volume displacement techniques were used in 74.7% of the patients, involving the Wise pattern (n=54, 96.4%) and the Grisotti technique (n=2, 3.6%). Volume replacement techniques were used in 25.3% of patients, involving the TDAP-flap (n=18, 94.7%) and a bilobed swing (n=1, 5.3%). Follow-up time varied from one to four years. Baseline characteristics were compared between patients who underwent OPS with volume replacement versus volume displacement. A significant difference (P<0.001) between the groups was found in the tumor location, with 17 out of 19 tumors (90%) located in the cranio-lateral quadrant in the volume replacement group while the tumors were more equally distributed in the volume displacement group. Furthermore, 20 patients (35.7%) in the volume displacement group versus only one patient (5.3%) in the volume replacement group underwent a contralateral symmetrization (P<0.01). In all patients, tumor- and surgical characteristics are depicted in Table 1. Postoperative complications Overall, an 18.7% clinically relevant complication rate was found, of which 14.7% had a CD score of 2, and 4% had a CD score of 3. Hematoma and wound dehiscence were reported in one patient (1.3%). Necrosis occurred in two patients (2.7%). An SSI was found in ten patients (13.3%) and led to a CD score of 3 in three patients (4%). No other complications led to a CD score of 3. The presence of seroma never resulted in a CD score of 2 or more. There was no significant difference in complications between the volume replacement and volume displacement groups. Re-excision rates after OPS were similar in both groups: 5.4% in the volume displacement group and 5.3% in the volume replacement group.

23 Outcomes following oncoplastic breast surgery Table 1. Preoperative and surgical characteristics of the total group, volume displacement and volume replacement Preoperative characteristics Total (n=75) Volume displacement (n=56) Volume replacement (n=19) P-value Age, years 61.0 (52.0-67.0) 59.5 (52.0-67.0) 62.0 (51.5-68.0) 0.985 BMI, kg/m2 27.0 (24.0-30.1) 27.1 (24.1-30.1) 26.1 (23.8-30.3) 0.950 Cup size 0.339 A,B,C 32 (42.7) 23 (41.1) 9 (47.4) D,E,H,F 33 (44.0) 27 (48.2) 6 (31.6) Missing 10 (13.3) 6 (10.7) 4 (21.1) ASA score 0.492 1 6 (8.0) 5 (8.9) 1 (5.3) 2 62 (82.7) 47 (83.9) 15 (78.9) 3 7 (9.3) 4 (7.1) 3 (15.8) Comorbidity 57 (76.0) 41 (73.2) 16 (84) 0.535 Current smoker 6 (8.0) 3 (5.4) 3 (15.8) 0.166 Tumor focality 1.000 Unifocal 62 (82.7) 46 (82.1) 16 (84.2) Multifocal 13 (17.3) 10 (17.9) 3 (15.8) Tumor size combined, mm 25 (20.5-35.0) 24.5 (19.5-34.0) 25.0 (23.0-33.5) 0.609 Location tumor 1 <0.001 Cranial 5 (6.7) 5 (9) 0 (0) Craniomedial 8 (11) 8 (15) 0 (0) Craniolateral 29 (39) 12 (22) 17 (90) Caudal 4 (5) 4 (7) 0 (0) Caudolateral 9 (12) 8 (15) 1 (5) Caudomedial 11 (15) 11 (20) 0 (0) Retro-areolar 1 (1) 1 (20) 0 (0) Medial 7 (10) 6 (11) 1 (5) Location tumor 2 0.118 Craniomedial 2 (15.4) 2 (20) 0 (0) Craniolateral 4 (30.8) 1 (10) 3 (100) Caudal 1 (7.7) 1 (10) 0 (0) Caudolateral 1 (7.7) 1 (10) 0 (0) 2

24 Chapter 2 Table 1. Continued Preoperative characteristics Total (n=75) Volume displacement (n=56) Volume replacement (n=19) P-value Caudomedial 1 (7.7) 1 (10) 0 (0) Medial 4 (30.8) 4 (40) 0 (0) Neoadjuvant chemotherapy 18 (24.0) 12 (21.4) 6 (31.6) 0.370 Neoadjuvant hormone therapy 3 (4.0) 3 (5.4) 0 (0.0) 0.567 Contralateral symmetrization 21 (28.0) 20 (35.7) 1 (5.3) 0.011 Surgical characteristics Total (n=75) Volume displacement (n=56) Volume replacement (n=19) P-value Operative time, min 108 (90-129) 105 (89-126) 117 (103-136) 0.061 Weight resected specimen, gram 84 (46-102) 80 (45-94) 98 (46-135) 0.469 Reduction weight, gram - 147 (45-305) - Sentinel node 67 (89.3) 51 (91) 16 (84) 0.360 Adjuvant radiotherapy 70 (93.3) 52 (95) 18 (95) 1.000 Adjuvant chemotherapy 20 (26.7) 17 (30) 3 (16) 0.249 Adjuvant hormone therapy 40 (53.3) 30 (54) 10 (53) 1.000 Data are n (%) or median (IQR). Significant P-values are denoted in italic. ASA indicates American Association of Anesthesiologists; BMI, body mass index; DCIS, ductal carcinoma in situ. BREAST-Q questionnaire Fifty-two patients completed the BREAST-Q questionnaire. Of these patients, only 34 (65.4%) filled out the domain ‘sexual well-being’. The domains ‘satisfaction with breasts’, ‘satisfaction with information about the surgery’ and ‘satisfaction with plastic surgeon’ were filled out by 51 patients (98.1%). Al other domains were fully completed. The median time from surgery until completion of the BREAST-Q was 28 months (IQR: 16-39 months). The BREAST-Q scale scores were compared between OPS with volume replacement and volume displacement. Women who underwent volume displacement techniques reported significantly higher scores for ‘physical well-

25 Outcomes following oncoplastic breast surgery being of the chest’, than patients who underwent volume replacement techniques (median 63 vs 38, P=0.003). Scores in all other domains were comparable. All the results for the BREAST-Q questionnaires are shown in Table 2. BREAST-Q scores of patients with and without complications were compared. Patients without complications had significantly higher scores in the domain ‘satisfaction with the breast’ and ‘satisfaction with information about the surgery’, compared to patients with complications (median 65 (IQR: 56-78) vs 56 (IQR: 43-53), P=0.007 and median 71 (IQR: 64-100) vs 55 (IQR: 46-78), P=0.026, respectively). In the other domains, no significant differences were seen. Table 2. Q scores BREAST-Q BCT domains for total cohort and stratified for volume replacement and volume displacement. Domain Total Volume replacement Volume displacement P-value Psychosocial well-being 63 (51-71) 64 (49-73) 56 (53-66) 0.453 Sexual well-being 56 (46-66) 58 (45-68) 56 (50-66) 0.838 Satisfaction with breasts 65 (55-74) 63 (55-70) 65 (54-83) 0.410 Physical well-being: chest 56 (38-66) 63 (45-71) 38 (20-53) 0.003 Satisfaction with information surgery 71 (59-91) 76 (64-96) 64 (49-76) 0.074 Satisfaction with plastic surgeon 100 (82-100) 100 (86-100) 87 (75-100) 0.173 Data are depicted in median and IQR. Significant P-values are denoted in italic. Patient self-assessment of cosmetic outcomes Fifty patients completed the self-assessment questionnaires for cosmetic outcomes. The individual global aesthetic judgment scores are presented in Table 3. A poor score was reported by two patients (4%), fair by five patients (10%), good by 18 patients (36%) and an excellent score by 25 patients (50%). This resulted in a median global aesthetic judgment score of 3.5. Scarring and areola-nipple symmetry scored 3.0, and breast symmetry scored 2.5. No significant difference was found between patients who underwent OPS with volume replacement versus volume displacement techniques (Table 4). Selfassessment scores in patients with and without complications were compared, showing a significantly higher score for symmetry in patients without complications (median 3.0 (IQR: 2.0-4.0) vs 1.0 (IQR: 1.0-2.0), P=0.001). In the other categories, no significant differences were observed. Panel evaluation of cosmetic outcomes In 40 patients medical photographs could be obtained that were amenable for panel evaluation, with a median postoperative time of 16 months (IQR: 8-43). 2

26 Chapter 2 Medical photographs were taken within the first postoperative year in 13 out of 30 patients (43%) and in three out of ten patients (30%) in the displacement and replacement group, respectively (P=0.456). Global aesthetic judgment scores distributed in the categories poor, fair, good and excellent are summarized in Table 3. The median scores by the specialists and laymen for global aesthetic judgment, symmetry of the breast, scarring, and areola-nipple symmetry are presented in Table 4. Table 3. Individual global aesthetic judgment scores, categorized as poor, fair, good and excellent, by patients and panel. Patient (n=50) Plastic surgeon 1 (n=40) Plastic surgeon 2 (n=40) Laymen 1 (n=40) Laymen 2 (n=40) Poor 2 (4.0) 3 (7.5) 2 (5.0) 5 (12.5) 10 (25.0) Fair 5 (10.0) 6 (15.0) 7 (17.5) 11 (27.5) 5 (12.5) Good 18 (36.0) 21 (52.5) 19 (47.5) 17 (42.5) 14 (35.0) Excellent 25 (50.0) 10 (25.0) 12 (30.0) 7 (17.5) 11 (27.5) Data are n (%). Table 4. Cosmetic outcomes for patients, plastic surgeons and laymen in the four categories. Total Volume replacement Volume displacement P-value Patient Global aesthetic judgment Symmetry Scar Areola-nipple symmetry* N=50 3.50 (3.00-4.00) 2.50 (1.00-4.00) 3.00 (3.00-4.00) 3.00 (2.50-4.00) N=12 3.00 (3.00-4.00) 3.00 (2.00-4.00) 3.00 (2.00-4.00) 4.00 (2.50-4.00) N=38 4.00 (3.00-4.00) 2.00 (1.00-3.00) 4.00 (3.00-4.00) 3.00 (2.00-4.00) 0.500 0.246 0.120 0.379 Specialist Global aesthetic judgment Symmetry Scar Areola-nipple symmetry** N=40 3.00 (2.50-3.50) 2.50 (2.00-3.00) 3.00 (3.00-3.50) 3.00 (2.50-3.50) N=10 3.00 (2.50-3.50) 3.00 (2.50-3.50) 3.00 (3.00-4.00) 3.50 (3.00-4.00) N=30 3.00 (2.50-3.50) 2.50 (2.00-3.00) 3.00 (3.00-3.50) 3.00 (2.50-3.50) 1.000 0.020 0.939 0.053 Laymen Global aesthetic judgment Symmetry Scar Areola-nipple symmetry** N=40 2.75 (2.00-3.50) 2.50 (1.00-3.00) 3.00 (2.00-3.50) 2.75 (2.00-3.50) N=10 2.75 (2.00-3.50) 3.00 (2.50-3.50) 2.25 (1.50-3.00) 3.00 (2.50-3.50) N=30 2.75 (2.00-3.50) 1.75 (1.00-3.00) 3.00 (2.00-3.50) 2.50 (2.00-3.50) 0.866 0.031 0.221 0.241 Numbers are median (IQR). For areola-nipple symmetry, numbers are lower than mentioned in the ‘total’ column because of exclusion criteria. *47 patients, 12 volume replacement, 35 volume displacement. ** 36 patients, 10 volume replacement and 26 volume displacement. Significant P-values are depicted in italic.

27 Outcomes following oncoplastic breast surgery The inter-observer agreement between laymen was fair to moderate, with a significant kappa value of 0.288, 0.478 and 0.372 for global aesthetic judgment, symmetry of the breast and scarring respectively. The agreement between specialists was also fair to moderate, with a kappa of 0.497, 0.236 and 0.357 for global aesthetic judgment, symmetry of the breast and scarring respectively. No significant agreement for areola-nipple symmetry was observed. Subgroup analysis between patients who underwent OPS with volume replacement versus volume displacement is presented in Table 4, showing a significantly higher symmetry score in the volume replacement group, according to the specialist and the laymen (median 3.0 vs 2.5 (P=0.020) and median 3.0 vs 1.75 (P=0.031) respectively). Cosmetic outcomes scored by the panel in patients with and without complications were compared. The laymen provided a significantly higher score for global aesthetic judgment in patients without complications (median 3 (IQR: 2.0-3.5) vs 2 (IQR: 1.0-3.0), P=0.046). The specialists provided a significantly higher score for symmetry in patients without complications (median 2.5 (IQR: 2.0-3.0) vs 2.5 (IQR: 1.5-2.0), P=0.002). In the other categories, no significant differences were observed. DISCUSSION In this study, postoperative complication rates, patient-reported outcomes and cosmetic outcomes were evaluated after OPS with volume displacement or volume replacement techniques, as well as the influence of the occurrence of complications on these outcomes. An overall clinically relevant complication rate of 18.7% was found in this study. Overall, patients were satisfied after their surgery. Cosmetic outcomes were scored as good to excellent by both patients and the panel in 60-86%. These results emphasize that OPS should be considered in eligible patients planned for oncological breast surgery. The occurrence of complications following breast surgery has a major impact on the patient’s life19, 20 and oncological treatment, as it might delay the start of adjuvant chemo or radiotherapy.21, 22 The current literature shows several studies about complication rates after OPS. However, these studies used various or no complication scoring systems and studies about the influence of complications on patient satisfaction are limited. Mattingly et al reported a total complication rate of 33.9% of which in 20.3% an intervention was required,23 in contrast to the substantially lower percentage of 4%, found in this current study. The study of Kronowitz et al reported a complication rate of 24% after immediate reconstructions, however, the severity of complications was not specified.24 2

28 Chapter 2 Patient satisfaction is considered an important outcome measure following OPS, which was evaluated with the BREAST-Q BCT module in this study. In all domains, scores were above average. The lowest scores were found in the domains ‘sexual well-being’ and ‘physical well-being of the chest’, both with a median score of 56, with ‘sexual well-being’ having a lower response rate (65.4%). This is similar to the findings in the study by Rose et al,25 where they compare BREAST-Q outcomes after OPS and breast-conserving surgery. Overall, patients were satisfied with their breasts and with psychosocial well-being, with a median score of respectively 65 and 63 in these domains. However, other studies on this topic showed better outcomes as compared to this present study.26, 27 Yet, there are notable differences compared to our study: patients were either younger, various types of reconstructions were included or small breasts (cup B or smaller) were excluded. When evaluating global aesthetic judgment, patients were satisfied with a score from fair to excellent in 96%, which was 75-95% by panel evaluation. This was in line with a study by Clough et al,28 in which a panel used a similar grading system to evaluate cosmetic outcomes of 101 breast cancer patients who underwent OPS with volume displacement, at two and five years follow-up 88% and 82% scored fair to excellent. The baseline comparison between volume replacement and volume displacement, showed significant differences in the location of the tumor and in contralateral symmetrizations. This was expected as the volume replacement technique is most often used in patients with smaller breasts and laterally located tumors, where adjacent tissue is used to fill the defect, leading to little asymmetry without the need for contralateral symmetrizations. No differences in complications were found between the groups. After volume replacement a lower score in the BREAST-Q domain ‘physical well-being of the chest’ (median score 38 vs 63) was reported, which is probably due to the more extensive surgery and the donor site morbidity, compared to the displacement group. As expected, subgroup analysis showed a significant higher score of mammary symmetry in the volume replacement group (median 2.8 vs 2.2, P=0.048). Outcomes of patients with and without clinically relevant complications were compared. BREAST-Q results showed that patients with complications were less satisfied with the breast and with the information about the surgery. The need for adequate preoperative information was emphasized in previous research in which patients after failed breast reconstructions were interviewed.29 As for cosmetic outcomes, patients with complications had lower mammary symmetry scores, reported by the patients and specialists, and lower global aesthetic judgment scores, reported by the laymen. Presented results imply that complications have a negative impact on patient satisfaction and on the cosmetic outcomes after

29 Outcomes following oncoplastic breast surgery OPS. This is in line with recent research, including 1871 breast cancer patients after various procedures in which the EQ-5D questionnaire was used to value the effect of surgical complications. This study showed that complications resulted in poorer health-related quality of life.30 Furthermore, complications leading to inferior cosmetic outcomes were expected, as they may lead to skin retractions contributing to asymmetry or a lower global aesthetic judgment, even though the expected influence on scarring was not found. There are several limitations of this study. First of all, the data were obtained in one study center, and may not be generalizable to the oncoplastic reconstructive population at large. Second, patients completed the BREAST-Q at variable time points after surgery, which could lead to recall bias, especially for the patient reported experience measures. Furthermore, no preoperative BREAST-Q was available for comparison. Third, patient reported cosmetic outcomes and the cosmetic panel evaluation were assessed at different time points and no explanation of the given score was obtained. Fourth, general quality of life, next to breast related quality of life, was not assessed in this study. Finally, the small sample size and limited number of available postoperative photographs (57.1%) resulted in the inability to accurately assess for confounding, such as patient characteristics, surgical characteristics and adjuvant therapies. Future studies, preferably with a larger sample size and multicenter design, should implement both BREAST-Q and medical photographs in a standard protocol, involving more frequent and fixed time points. In conclusion, postoperative complications were observed in 18.7% of patients after OPS, which required (surgical) intervention in only in 4%. No differences in complication rates were observed between techniques. Furthermore, 60-86% of cosmetic outcomes were scored good to excellent, in which patients given the highest scored followed by the plastic surgeons and laymen. Volume displacement or replacement was performed for different indications and generally showed comparable results. Expected differences in physical discomfort and symmetry between both techniques were observed. The occurrence of complications resulted in lower BREAST-Q scores and cosmetic outcome scores. Ultimately, these insights could be used to thoroughly counsel patients by using information from patient, specialist and laymen experience. 2

30 Chapter 2 REFERENCES 1. Kaufman CS. Increasing Role of Oncoplastic Surgery for Breast Cancer. Curr Oncol Rep 2019; 21(12):111. 2. Franceschini G, Terribile D, Magno S, et al. Update on oncoplastic breast surgery. Eur Rev Med Pharmacol Sci 2012; 16(11):1530-40. 3. Heeg E, Jensen MB, Hölmich LR, et al. Rates of re-excision and conversion to mastectomy after breast-conserving surgery with or without oncoplastic surgery: a nationwide population-based study. Br J Surg 2020; 107(13):1762-1772. 4. van Maaren MC, de Munck L, de Bock GH, et al. 10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study. Lancet Oncol 2016; 17(8):1158-1170. 5. Gardfjell A, Dahlbäck C, Åhsberg K. Patient satisfaction after unilateral oncoplastic volume displacement surgery for breast cancer, evaluated with the BREAST-Q™. World J Surg Oncol 2019; 17(1):96. 6. Kouwenberg CAE, Kranenburg LW, Busschbach JJ, Mureau MAM. Why BreastConserving Therapy Should be Considered Treatment of Choice in Early-Stage Breast Cancer Patients. Ann Surg Oncol 2021; 28(13):8017-8019. 7. Yang JD, Lee JW, Kim WW, et al. Oncoplastic surgical techniques for personalized breast conserving surgery in breast cancer patient with small to moderate sized breast. J Breast Cancer 2011; 14(4):253-61. 8. Noguchi M, Yokoi-Noguchi M, Ohno Y, et al. Oncoplastic breast conserving surgery: Volume replacement vs. volume displacement. Eur J Surg Oncol 2016; 42(7):926-34. 9. Hakakian CS, Lockhart RA, Kulber DA, Aronowitz JA. Lateral Intercostal Artery Perforator Flap in Breast Reconstruction: A Simplified Pedicle Permits an Expanded Role. Ann Plast Surg 2016; 76 Suppl 3:S184-90. 10. Hamdi M, Van Landuyt K, Hijjawi JB, et al. Surgical technique in pedicled thoracodorsal artery perforator flaps: a clinical experience with 99 patients. Plast Reconstr Surg 2008; 121(5):1632-1641. 11. Schwartz JD. New Approach to Oncoplastic Breast Conservation: Combining Autologous Volume Replacement and the Wise-pattern Mammaplasty. Plast Reconstr Surg Glob Open 2018; 6(10):e1987. 12. von Elm E, Altman DG, Egger M, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Bmj 2007; 335(7624):806-8. 13. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama 2013; 310(20):2191-4. 14. Johnson M, Cook L, Rapisarda FI, et al. Oncoplastic breast surgery technique for retroareolar breast cancer: a technical modification of the Grisotti flap in patients with short nipple to inferior mammary crease distance. J Surg Case Rep 2020; 2020(9):rjaa285. 15. Kim MS, Lee SK, Jue MS, Park HJ. The Reappraisal of the Slide-Swing Skin Flap: A Versatile Technique for Surgical Defects. Ann Dermatol 2019; 31(5):525-529. 16. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240(2):205-13. 17. Pusic AL, Klassen AF, Scott AM, et al. Development of a new patient-reported outcome measure for breast surgery: the BREAST-Q. Plast Reconstr Surg 2009; 124(2):345-353. 18. Massa M, Meszaros P, Baldelli I, et al. Aesthetic evaluation in oncoplastic and conservative breast surgery: a comparative analysis. Plast Reconstr Surg Glob Open 2015; 3(3):e339.

RkJQdWJsaXNoZXIy MTk4NDMw