Breast reconstruction and neoadjuvant radiotherapy (BRENAR) – study protocol for a multicenter, prospective, single-arm pilot study

Abstract

Background:

Over the past decade, post-mastectomy radiotherapy (PMRT) is indicated more frequently in breast cancer treatment, especially in patients with involved axillary lymph nodes. However, PMRT is associated with high complication rates and less satisfactory cosmetic results when combined with immediate breast reconstructions. This has led to ongoing controversy regarding breast reconstruction and radiotherapy, often postponing the reconstruction until long after PMRT has been completed. Preoperative radiotherapy, also known as neoadjuvant radiotherapy (NART), is emerging as a safe and promising alternative with the potential to allow immediate reconstruction without the negative effects of radiotherapy on the reconstructed breast. However, data on the complication rates and patient-reported outcomes (PROs) after NART followed by mastectomy and breast reconstruction are still limited.

Methods:

This is a multicenter, prospective, single-arm pilot study including breast cancer patients requiring mastectomy and PMRT, who desire immediate breast reconstruction, either implant-based or autologous. The primary objective is to assess complications three months after the last planned reconstructive surgery. The secondary objectives are to evaluate patient-reported health-related quality of life (HR-QoL), patient- and physician-reported cosmetic results, and pathological response.

Discussion:

The primary outcome of this pilot study is to provide further evidence to determine whether NART is a viable alternative to PMRT in terms of complication rates when combined with immediate breast reconstruction. The secondary outcomes will enhance our understanding of patients’ HR-QoL and cosmetic outcomes. If NART proves to be a safe alternative, this pilot study will lay the foundation for a national multicenter randomized controlled trial to evaluate long-term HR-QoL and oncological outcomes.

Breast cancer treatment often requires a multimodal approach that may include (neo)adjuvant systemic therapy, surgery, and radiotherapy. Post-mastectomy breast reconstruction has become an essential part of treatment, as it significantly improves health-related quality of life (HR-QoL), body image, and sexual well-being, especially when performed in the same surgery as the mastectomy (i.e., immediate breast reconstruction (IBR))^[1,2]. IBR prevents patients who desire a reconstruction to live without a breast contour for a certain amount of time and, if oncologically safe, allows for their own skin and nipple to be spared, resulting in superior cosmetic outcomes^[1-3].

Postmastectomy radiotherapy (PMRT) has shown to reduce locoregional recurrences and enhance patient survival, particularly in patients with involved axillary nodes^[4-6]. In addition, indications for PMRT have broadened over the last decade due to substitution of axillary lymph node dissection by axillary radiotherapy^[5,7], resulting in more patients undergoing PMRT. However, PMRT is known to significantly increase both early and late complication rates when combined with immediate breast reconstruction, especially when breast implants are used^[8,9]. Therefore, in The Netherlands, IBR is typically avoided if there is a slight risk of PMRT^[10]. In implant-based reconstruction, major complications requiring surgical revision have been observed in up to 40% of irradiated implants compared to 20% of unirradiated implants, with severely impacted HR-QoL and cosmetic outcomes^[8].

For autologous reconstructions, as shown in a meta-analysis by Schaverien et al^[11], significantly higher rates of fat necrosis, fibrosis, and volume loss were observed after PMRT compared to unirradiated patients. Therefore, when autologous reconstructions are chosen, PMRT is typically administered directly after mastectomy, and reconstruction is delayed for several months to years to minimize the adverse effects of radiotherapy on the flap. This subjects patients to an extended period without a breast contour and a second major surgical procedure, both of which have been shown to negatively affect HR-QoL, body image perception, and sexual well-being during their treatment^[1,2]. Although on the long term, no difference in patient satisfaction is seen between IBR and delayed reconstructions^[12,13].

These high complication rates and unsatisfactory cosmetic results have led to controversy and large (inter)national practice variation^[10,14-19], where the experience and preference of the plastic surgeon and radiation oncologist often lead to decisions on the timing and type of reconstruction, instead of patient preferences or high-quality, unbiased scientific evidence^[10,14-19]. Thus, a clear solution that allows immediate breast reconstruction in combination with radiotherapy (RT) without high complication rates is needed. In particular, IBR results in superior cosmetic outcomes, body image perception, and HR-QoL in patients with an uncomplicated course^[1-3]. Furthermore, compared to delayed reconstruction, the overall treatment time for IBR is often significantly shorter (6–12 months), and there is no need to undergo a second major surgery to complete the reconstruction^[3].

Neoadjuvant RT (NART) is gaining momentum in breast cancer treatment, similar to other types of cancer where NART has become part of standard care (e.g., rectal cancer and sarcoma)^[20-22]. This new treatment strategy is promising to be safe for breast cancer from an oncological perspective^[23,24], with superior cosmetic outcomes and decreased complication rates in IBR^[24-26], thereby potentially minimizing the future need for delayed breast reconstruction. However, due to a lack of randomized controlled trials (RCTs) with direct comparisons between available reconstructive techniques, and only studies with a small sample size, controversy, and wide practice variations remain. Furthermore, these current study results were heavily influenced by specific expertise, local experience, and heterogeneous radiotherapy protocols. Recently two small studies with prospective data have been performed assessing NART and immediate autologous reconstruction (i.e., PRADA and Schaverien et al)^[24,26]. However, in breast reconstructive surgery most woman opt for implant-based reconstruction^[8,10,15]. Therefore, we would like to perform the breast reconstruction and neoadjuvant radiotherapy (BRENAR) multicenter pilot study on NART and all options for breast reconstruction based on Dutch guidelines and, if results are positive, subsequently commit to a larger national, multicenter RCT.

We hypothesize that NART compared to PMRT will lead to better cosmetic results with better HR-QoL than PMRT for the following reasons: 1) it allows for IBR, which is known to yield superior results compared to delayed reconstruction, and 2) it avoids the negative effects of PMRT on the skin/underlying tissue of an autologous flap or the capsule of the implant, thus leading to fewer complications. Therefore, we designed a study protocol for a multicenter, prospective, non-randomized pilot study in The Netherlands. If we can confirm similar complication rates of NART as compared to PMRT (i.e., ≤40%), a large national RCT will be performed to investigate long-term HR-QoL, cosmetic outcomes, and oncologic results of NART combined with mastectomy and immediate breast reconstruction.

Objectives

The primary objective is to investigate whether the incidence of major postsurgical complications up to 3 months after NART, mastectomy, and IBR will be equal to or below the current rate of 40% after mastectomy^[8], PMRT, and IBR.

The secondary objectives are to determine patient-reported outcomes (PROs) measured in terms of satisfaction and cosmetic results at 3 months after definitive breast reconstruction, physician-reported cosmetic results at 3 months after definitive breast reconstruction, timely initiation of adjuvant systemic therapy (if applicable), pathologic response assessed in mastectomy specimens, and minor surgical complications up to 3 months after mastectomy and IBR.

Methods/design

Pilot study design

This study will be conducted as a prospective, multicenter, single-arm, interventional pilot study. Six Dutch hospitals agreed to participate. The study was approved by the Dutch Medical Ethics Assessment Committee NedMec (METC) on 20 December 2022 and registered on clinicaltrials.gov on 1 February 2022.

Eligibility

Patients are eligible for inclusion if they have an indication for mastectomy and at least chestwall RT, and want an IBR, either implant-based or autologous. Detailed inclusion and exclusion criteria are shown in Table 1. Before proceeding with treatment, as part of the standard care in The Netherlands, all patients will be discussed in a specialized multidisciplinary breast cancer meeting to determine the standard of care treatment plan and assess study eligibility. If eligible, patients will be offered the intervention under the study protocol (i.e., NART followed by mastectomy and IBR). If they decline, they will receive standard of care.

Table 1.

Inclusion and exclusion criteria

Inclusion criteria	Female
	≥18 years of age
	WHO performance scale ≤2
	Adequate communication and understanding of the Dutch language
	Able to understand and write Dutch written informed consent
	Indication for skin sparing mastectomy and a known indication for radiotherapy of at least the chest wall
	Stage III (cT3N1, cT0-2N2-3) or cN1 with more than 3 suspicious nodes at initial diagnosis A positive SN/MARI* pre-breast surgery in case of: cT1-2N0 and less than 3 RFa at initial diagnosis and cCR on imagingb cT3N0 and no RF at initial diagnosis ypN0, but cT3N0 and at least 1 RF at initial diagnosis ypN0, but cT1-2N0 and at least 3 RF at diagnosis and no pCR
Exclusion criteria	Legal incapacity
	Not able to understand or sign Dutch written informed consent
	Previous history of breast cancer or another malignancy for which RT of the breast and/ or axilla
	Collagen synthesis disease
	Age <18 years
	Pregnant or lactating
	Smoking
	BMI >35 kg/m2
	cT4 tumor
	Skin sparing mastectomy not possible
	If NAC in cT1-2N0 and 3 RFa: in triple negative or Her2 positive and no tumor cells in preoperative biopsy
	No indication for RT after the SN/MARI results

WHO World Health Organization, SN/MARI sentinel node and/or marking axilla with radioactive iodine seeds, RF risk factors, cCR clinically complete response, RT radiotherapy, MRI magnetic resonance imaging, BMI body mass index, NAC neo-adjuvant chemotherapy.

^*If the RT indication is not yet clear a SN/MARI procedure will be performed.

^aRF: (lympho-)vascular invasion, Grade III, age ≤40 years, triple negative.

^bIn patients with cT1-2N0 and at least 3 RF a tumour biopsy can be considered prior to surgery in case of NAC, since in case of no pathological complete response the indication for RT is already set and a SN/MARI prior to breast surgery is not required.

Study outcomes

Our main study outcome is the proportion of patients with major postsurgical complications at 3 months, defined as any adverse event requiring readmission or reoperation. The 3 month interval is chosen, because the most severe complications occur within this timeframe^[5,26].

These major complications will be categorized as infection, hematoma, loss of flap/ implant/expander, and (fat) necrosis. Our additional study outcomes will be minor complications, patient-reported satisfaction as measured with the BREAST-Q, physician-reported cosmetic results (based on breast photographs obtained as part of standard care)^[27], pathological complete response (pCR) based on the mastectomy specimen, and timely initiation of relevant adjuvant therapy (e.g., systemic therapy). Digital photographs of the breast and donor site will be compared with photographs taken at baseline and three months after mastectomy with IBR, which will be used for physician-reported cosmetic assessment. The study phases and data collection processes are shown in Fig. 1.

Figure 1.

Flowchart of study phases and data collection. (A) No neoadjuvant systemic therapy. RT radiotherapy, SN sentinel node, ALND axillary lymph node dissection, SSM skin-sparing mastectomy. (B) Neoadjuvant systemic therapy. RT radiotherapy, SN/MARI sentinel node and/ or marking axilla with radioactive iodine seeds, ALND axillary lymph node dissection, pCR pathological complete response, SSM skin-sparing mastectomy.

At baseline, the following demographic characteristics of the patients will be obtained: age (years), BMI (kg/m2), smoking status (previous smoker, if current smoker: exclusion), diabetes, and hypertension. Additionally, relevant tumor and treatment characteristics will be scored during follow-up, such as laterality (uni- or bilateral), extent of disease (TNM 8 classification), pathological characteristics such as differentiation grade, presence of lymphovascular invasion, presence of pCR (no, partial, near pCR, pCR)^[28], number of involved and resected lymph nodes, systemic therapy, mastectomy type (skin sparing (SSM), nipple-sparing mastectomy (NSM), or combined), whether a sentinel node (SN)/marking the axilla with radioactive iodine seed (MARI) and/or targeted axillary dissection (TAD) procedure was performed, acellular dermal matrix use, lipofilling use, type of autologous flap, type of tissue expander/implant brand and positioning (subcutaneous or submuscular), and RT-target volumes including dose-volume parameters.

Treatment and study procedures

After diagnosis, patients will be treated according to Dutch national guidelines. Most eligible patients will first be treated with neoadjuvant systemic treatment (NAST); however, patients not undergoing NAST may also be eligible. Patients will be asked for informed consent when there is an indication for mastectomy, a wish for an IBR, and a (potential) indication for RT. Subsequently, an SN and/or MARI-/TAD-procedure^[29] will be performed for axillary staging since this may have implications for the indication and target volumes for radiotherapy. In addition, in the case of neoadjuvant systemic therapy, when the SN or MARI/TAD nodes do not contain tumor cells, vacuum-assisted core tumor biopsies will be performed to exclude patients who would have a pCR^[30]. Thus, the patient will be eligible only if the biopsy shows residual tumor. Once the indications for adjuvant systemic treatment and RT, including its target volumes, are determined, and the patient has provided written informed consent for study participation, she will be included in the study.

In the case of NAST, NART will start six to eight weeks after the last course of systemic therapy, following current national guidelines. NART will consist of 5 × 5.2 Gy in one week in patients ≥50 years of age and without indications for nodal RT, and with 15 × 2.67 Gy in three weeks in cases of <50 years or an indication for nodal RT. RT will be delivered using forward or inverse intensity-modulated RT or a hybrid technique combining tangential fields with volumetric arc therapy. RT dosimetry will have to fulfill national consensus^[31]. No tissue-equivalent material to increase the skin dose will be allowed since patients with cT4 disease are excluded^[32]. Two to six weeks after NART, SSM will be performed, and if possible, the nipple-areola complex will also be spared. The technique and type of reconstruction are chosen according to standard clinical procedures in the participating centers.

The type of breast reconstruction will be decided by the patient and the plastic surgeon during the shared decision-making process at the outpatient clinic. An IBR will be performed in the same surgery session as the SSM. Breast reconstruction may consist of an autologous flap or silicone implants (either in one- or two-stage). In the case of a two-stage procedure, a tissue expander will be temporarily placed, whereafter a change to the definitive implant will occur three to six months later, according to standard procedures in participating hospitals.

At standard surgical follow-up intervals and three months after receiving definitive reconstructive surgery, the patient will be seen at the outpatient clinic to evaluate surgical complications. Additional measurements, such as PROs at three months, will be collected using email or regular mail (based on patient preferences).

Sample size calculations

We have chosen to include 20 patients over an estimated recruitment period of 36 months. Based on statistics from previous years at the participating centers, approximately 25 patients are estimated to be eligible for inclusion in this study every two years. A sample size of 20 patients is chosen to account for possible refusal and ineligibility during the study. This sample size is chosen according to the IDEAL framework, as we consider this a Phase 2a study^[33], and is thus considered sufficient to evaluate safety, improve the intervention, address clinical challenges, and gain a better understanding of complications and patient experiences.

Statistical analyses

The data will be analyzed and presented using descriptive statistics. Since this is a study with a small sample size, no formal statistical testing will be performed. Outcomes will be presented as frequencies and percentages for categorical variables, median with interquartile range (IQR) for non-normally distributed continuous variables, and mean with standard deviation (SD) for normally distributed continuous variables. All analyses will be performed using SPSS (SPSS Statistics 26.0, IBM Corp., Armonk, NY, USA).

Recruitment, consent, and withdrawal

Eligible patients will be approached by treating physician/nurse practitioners for participation in the study. All patients will be informed of the study goals, procedures, potential hazards, and the treatment allocation process. Potential participants will have one week to consider their decisions and ask additional questions. Written informed consent for study participation will be obtained by a member of the research team (i.e., the local treating physician, nurse practitioner, or researcher). The patients will receive a copy of the informed consent form, and their participation will be documented in their electronic health record (EHR).

Study data management, oversight, publication and future perspectives

Data handling and protection will be conducted according to ISO 27001-compliant processes and ICH GCP20^[34,35], as well as applicable regulations. Confidentiality will be maintained at all times, and participant information will not be disclosed to third parties. No directly identifiable data will be collected, and the pictures will not contain a face. Indirect identifiable data (medical data) will be handled confidentially and processed using pseudonymization. Data will be extracted from EHRs into an electronic Case Report Form using the UMCU-endorsed system Castor EDC^[36], with each patient assigned a personalized, unique identifier. Adverse events will be reported according to the Common Terminology Criteria for Adverse Events (CTCAE). The study procedures will be monitored by an independent qualified Clinical Research Office (Julius Clinical, Zeist, The Netherlands) in accordance with the Dutch Federation of Academic hospitals-guidelines and good clinical practice. . The results will be submitted to peer-reviewed journals, and insurance will be provided for all participants in accordance with Dutch legislation.

Discussion

Worldwide, there is substantial variability and inconsistency in breast reconstruction practices when PMRT is necessary.^[10,14-19]. NART is a promising alternative to PMRT, with several studies showing similar oncological outcomes^{[23-25,37-40]}, including two prospective studies demonstrating its safety and feasibility in node-positive and locally advanced breast cancer^[24,25]. The BRENAR pilot study aims to investigate possible complications of NART followed by mastectomy with IBR. Our pilot study will be unique by also including patients with a wish for implant-based reconstructions. We expect to find similar or possibly lower complication rates than currently seen in breast reconstructions followed by PMRT (40%)^[8]. If this study proves that NART is safe and yields acceptable complications rates (i.e., ≤40%) for patients undergoing IBR, it will lay the foundation for a larger, prospective, national multicenter RCT.

NART is routinely used for other types of cancer, such as rectal cancer, esophageal cancer, and sarcomas, with comparably improved complication rates compared with adjuvant RT^[20-22]. A recent systematic review compared outcomes after autologous breast reconstruction and several radiotherapy strategies including PMRT and NART^[14]. Similar overall short- and long-term complications were found between the two, but very few studies reported on NART. Another systematic review focused on the safety and feasibility of NART in combination with IBR^[41] and found an overall complication rate of 3–36%, with one study specifically showing no increase in complications compared with adjuvant RT^[38]. Furthermore, the first long-term cosmetic outcomes from the PRADA study showed superior cosmetic results compared with PMRT^[25].

Overall, these studies suggest a favorable treatment effect of NART, while ensuring safety from an oncological perspective. However, all available studies had important limitations and expressed the need for further prospective evaluation. Thus, more prospective data and large-scale international RCTs are required to provide more definitive evidence. In the national RCT we are eventually aiming for, we will also collaborate with members of the newly founded international consortium for NART and all participating countries will follow the same standards and protocols, assessing HR-QoL and cosmetic satisfaction using the BREAST-Q as the main endpoint. Data from all these trials will be pooled to reach sufficient power for oncological endpoints and subgroup analyses of PROs of the different breast reconstruction techniques (i.e., autologous, one-stage implant-based, and two-stage implant-based). Funding for the RCT has been granted in Belgium, and this study is expected to start recruitment end of 2024. In The Netherlands, we will await the results of our pilot study before proceeding with an RCT. Efforts are also underway in Switzerland and the UK to secure funding, with the intention of collaborating closely with our study team.

We believe that using RT in a neoadjuvant setting could potentially result in a shorter overall locoregional treatment time from diagnosis to completion. Additionally, patients undergoing NART may experience fewer complications and a better patient-reported HR-QoL and cosmetic satisfaction.

Limitations

This pilot study will include a small sample of 20 patients and will assess the complications and feasibility of this emerging technique. However, the study design is non-randomized, which may have introduced a selection bias. Randomization will be performed in the aspired larger follow-up trial (NART vs. PMRT), aiming to reduce selection bias. In both groups, an SN/MARI procedure will have to be performed before definitive inclusion. Currently, mastectomy and SN procedures are usually performed during the same surgical procedure. However, our study requires separate surgical procedures to conclusively determine the RT volumes and, sometimes, indication. Another burden can be additional tumor biopsy after NAST to determine whether residual disease is present in cases of inconclusive or negative SN/MARI (Fig. 1). Consequently, some patients who provide informed consent for NART will be excluded from this study because RT indications no longer apply.

Study status

This article is based on the protocol version 3.0, dated 13 May 2024. The first patient has been recruited at the UMC Utrecht in April 2023. The approximate date on which recruitment will be completed is the end of 2026.

Trial registration:

The breast reconstruction and neoadjuvant radiotherapy (BRENAR) study is registered with the Central Committee on Research Involving Human Subjects (CCMO) on 20 December 2022.

Ethical approval

Ethical approval was obtained on 20 December 2022, by the Dutch Medical Ethics Assessment Committee NedMec (METC) and is registered on clinicaltrials.gov.

Consent

Written informed consent was obtained from the participating patients. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

Dr Danny A. Young-Afat obtained Innovation Grant by Cancer Center Amsterdam Foundation (Grant Number CCA2023-2-34).

Author contributions

S.H.N., D.Y.A., L.J.B., and W.M. wrote the first draft of the manuscript, and all co-authors read and approved the final manuscript. D.Y.A., L.J.B., and W.M. designed the pilot study and wrote most of the study protocol, with contributions from the listed coauthors in several stages.

Conflicts of interest disclosure

The authors declare that they have no conflict of interests.

Research registration unique identifying number (UIN)

None.

Guarantor

None.

Provenance and peer review

None.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.