PRADA-II

Overview

Each year in the UK, about 15,000 women undergo mastectomy and lymph node surgery. One in three have breast reconstruction, while others opt for implants or no reconstruction. Many patients also need radiotherapy, which can cause delays to treatment if complications arise after reconstruction, damage to the reconstruction, leading to firmness, shrinkage, unevenness, and discomfort. Because of this, many hospitals avoid immediate reconstruction if radiotherapy is required, leaving women to wait months, with two-thirds never receiving reconstruction at all. Research shows that giving radiotherapy before mastectomy and reconstruction is safe, equally effective for cancer control, and may preserve reconstruction quality. This approach could improve satisfaction with appearance and comfort, reduce treatment delays, and support faster recovery. Ultimately, better reconstruction outcomes can enhance body image, confidence, and overall well-being. This is a large study with 450 patients across 26 NHS hospitals to confirm these early findings. Radiotherapy before mastectomy and reconstruction will be compared to radiotherapy after mastectomy and reconstruction.

Objectives

Primary objective

To investigate whether pre-operative radiation leads to improved 2-year satisfaction with immediate autologous reconstruction compared to post-operative radiation.

Feasibility objective

To assess the feasibility of recruiting a sufficient number of patients, including: (a) the number of sites open and randomising patients, (b) number of patients randomised, (c) mean monthly recruitment, (d) % proportion of patients screened who proceeded to consent, (e) number of locally advanced breast cancers requiring mastectomy that are suitable for autologous reconstruction, and (f) proportion of patients consented who proceeded to be randomised.

Secondary objective

To determine if the pre-operative radiation improves overall health-related quality of life, attenuates treatment times, reduces fat necrosis, and increases pathological complete response rates. Further secondary objectives include recording oncologic outcomes, including local recurrence, distant metastatic spread, disease-free and overall survival.

Process evaluation objective

To identify facilitators and barriers to the implementation of pre-operative radiation, to develop appropriate implementation strategies, and to create an implementation blueprint to support deployment of the pre-operative radiation care pathway, if deemed appropriate.

Inclusion/ exclusion criteria

1. Women >= 18 years of age, diagnosed with biopsy-proven, locally advanced breast cancer defined by any of the following (derived from diagnostic imaging) based on the latest guidance from the American Joint Committee on Cancer Staging (2017):
   1.1. Tumour (T) stage T3 or T4 and any Nodal (N) stage
   1.2. Any T stage, N2 or N3 disease
   1.3. T2 and/or N1 disease with additional risk factors for local recurrence, including:
   1.3.1. Medial tumour thought to benefit from internal mammary radiation, and/or
   1.3.2. Chemoresistant disease (if ER negative and/ or HER-2 positive)
2. In addition:
   2.1. Patients must be suitable for autologous reconstruction using microsurgical techniques, including any of the following techniques:
   2.2. Deep Inferior Epigastric Perforator Flap (DIEP)
   2.3. Transverse Upper Gracilis (TUG) – or variation therein, including Diagonal Upper Gracilis (DUG) or L-Shaped Upper Gracilis (LUG)
   2.4. Superior or Inferior Gluteal Artery Perforator Flap (S-GAP or I-GAP, respectively)
   2.5. Lumbar perforator flaps
3. Multidisciplinary team recommends mastectomy regardless of response to upfront therapy (if required), either due to tumour size, multicentricity, or multifocality
4. Multidisciplinary team recommends post-mastectomy radiotherapy either due to tumour size or nodal status
5. Patients in whom upfront medical therapy has failed to facilitate breast conservation. The multidisciplinary team must agree that they need radiation after mastectomy, and they must be suitable candidates for microsurgical reconstruction
6. Multidisciplinary team has confirmed that they can define nodal radiation regions to be treated with available information

Key Exclusion

1. Pregnancy-associated breast cancer, including women known to be pregnant at diagnosis, patients with a positive pregnancy test at screening, and/or women who are lactating in whom radiation therapy is contraindicated
2. Metastatic disease since breast reconstruction remains controversial in these cases, and would confound survival outcomes. If metastatic disease is discovered after randomisation and prior to protocol interventions, then the participant will be discontinued from protocol interventions. Follow-up information will still be collected, including questionnaires and photos.
3. Biopsy-proven synchronous contralateral breast cancer
4. Inflammatory cancer or skin involvement precluding skin-sparing mastectomy
5. Mastectomy for biopsy confirmed local recurrence after breast conserving surgery since typically these patients have already received whole breast radiation therapy
6. Failed breast-conserving surgery cases, requiring mastectomy to ensure clear resection margins
7. Patients receiving nipple-sparing mastectomy due to attendant risks associated with nipple aerolar vascularity and nipple areolar necrosis
8. Bleeding dyscrasias and anticoagulation, which are relative contraindications to autologous microvascular anastomosis
9. Unable to give informed consent to the trial

Planned sample size:

450 patients across 30 sites with LABC undergoing IMBR and RT. This is based on a superiority margin between groups defined as an absolute increase in BREAST-Q satisfaction with breasts at 2 years of 6-points.

Total number of sites planned:

30 sites

Timeline:

Estimated recruitment between March 2026 – Feb 2029