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Pre-operative Radiotherapy And Deep Inferior Epigastric artery Perforator (DIEP) flAp study (PRADA): Aesthetic outcome and patient satisfaction at one year.

Open AccessPublished:January 19, 2023DOI:https://doi.org/10.1016/j.bjps.2022.11.040

      Abstract

      Introduction

      : The optimal combination of radiotherapy and breast reconstruction has not yet been defined. Postmastectomy radiotherapy (PMRT) has deleterious effects on breast reconstruction leading to caution amongst surgeons. Pre-operative radiotherapy (PRT) is a growing area of interest, is demonstrated to be safe and spares autologous flaps from radiotherapy. This study evaluates the aesthetic outcome of PRT and DIEP flap reconstruction within the PRADA cohort.

      Methods

      : PRADA was an observational cohort study designed to evaluate the feasibility and safety of PRT for women undergoing neoadjuvant chemotherapy (NACT) and DIEP reconstruction. Panel evaluation of 3D surface images (3D-SI) and patient-reported outcome measures (BREAST-Q) for a subset of women in the study were compared with those of a DIEP-PMRT cohort who had undergone DIEP reconstruction and PMRT.

      Results

      : 17 out of 33 women in the PRADA study participated. 28 women formed the DIEP-PMRT cohort (median follow-up 23 months). Median [IQR] “satisfaction with breasts” score at 12 months for the PRADA cohort was significantly better than the DIEP-PMRT cohort (77 [72-87] versus 64 [54-71] respectively), p=0.01). Median [IQR] panel evaluation (5-point scale) was also significantly better for the PRADA cohort than for the DIEP-PMRT cohort (4.3 [3.9-4.6] versus 3.6 [2.8-4] p=0.003).

      Conclusions

      : Aesthetic outcome for the PRADA cohort was reported to be "good" or "excellent" in 93% of cases using a bespoke panel assessment with robust methodology. Patient satisfaction at one year is encouraging and superior to DIEP-PMRT at 23 months. Switching surgery-radiotherapy sequencing leads to similar breast aesthetic outcomes, and warrants further large-scale, multi-centre evaluation in a randomised trial.

      Key words

      Introduction

      The optimal integration of radiotherapy and breast reconstruction surgery timing and techniques has not yet been defined. Heterogeneity between studies regarding both surgical and radiotherapy approach, follow-up and primary end points make robust comparison challenging. Postmastectomy radiotherapy (PMRT) is offered to women with higher risk of locoregional recurrence and results in improved local regional control and survival.

      Early and locally advanced breast cancer: diagnosis and management. Evidence reviews for postmastectomy radiotherapy. In. National Institute for Health and Care Excellence: NICE guideline NG101; 2018.

      However PMRT has deleterious effects on the reconstructed breast leading to many women being advised against immediate reconstruction.
      • Duxbury PJ
      • Gandhi A
      • Kirwan CC
      • et al.
      Current attitudes to breast reconstruction surgery for women at risk of post-mastectomy radiotherapy: A survey of UK breast surgeons.
      It is now generally accepted that immediate reconstruction is preferable over delayed mainly due to the superior aesthetic outcome achieved by maintenance of the natural skin envelope. While awaiting delayed reconstruction women are affected by low emotional wellbeing, poor body image, and social distress.
      • Al-Ghazal SK
      • Sully L
      • Fallowfield L
      • et al.
      The psychological impact of immediate rather than delayed breast reconstruction.
      ,
      • O'Connell RL
      • Rusby JE
      • Sagha A
      • et al.
      Exploring the Lived Experience of Undergoing an Immediate Versus Delayed Deep Inferior Epigastric Artery Perforator (DIEP) Flap Reconstruction in Women Who Require Post-Mastectomy Radiotherapy.
      Autologous breast reconstruction is reported to be, on balance, the technique of choice given its lower rate of complications and reconstruction failure, acceptable flap survival rates,
      • Halyard MY
      • Wong WW
      • Vora SA
      • et al.
      Acute and chronic results of adjuvant radiotherapy after mastectomy and transverse rectus abdominis myocutaneous (TRAM) flap reconstruction for breast cancer.
      and cosmesis. The reported deleterious effects of radiotherapy on autologous reconstruction are flap volume reduction (12.3% with radiotherapy versus 2.6% without) and higher rates of fat necrosis,
      • Taghizadeh R
      • Moustaki M
      • Roblin P
      • et al.
      Does post-mastectomy radiotherapy affect the outcome and prevalence of complications in immediate DIEP breast reconstruction? A prospective cohort study.
      flap contracture,
      • He S
      • Yin J
      • Robb GL
      • et al.
      Considering the Optimal Timing of Breast Reconstruction With Abdominal Flaps With Adjuvant Irradiation in 370 Consecutive Pedicled Transverse Rectus Abdominis Myocutaneous Flap and Free Deep Inferior Epigastric Perforator Flap Performed in a Chinese Oncology Center: Is There a Significant Difference Between Immediate and Delayed?.
      and breast symptoms (including neo-breast pain, swelling, sensitivity and skin changes).
      • Cooke AL
      • Lambert P
      • Diaz-Abele J
      • et al.
      Radiation Therapy Versus No Radiation Therapy to the Neo-breast Following Skin-Sparing Mastectomy and Immediate Autologous Free Flap Reconstruction for Breast Cancer: Patient-Reported and Surgical Outcomes at 1 Year-A Mastectomy Reconstruction Outcomes Consortium (MROC) Substudy.
      Some women experience minimal PMRT reconstruction complications whilst others suffer major complications, some resulting in reconstruction failure, this unpredictability leads to caution among surgeons.
      The use of pre-operative or neoadjuvant radiotherapy (PRT) is a growing area of interest in breast cancer treatment.
      • Lightowlers SV
      • Boersma LJ
      • Fourquet A
      • et al.
      Preoperative breast radiation therapy: Indications and perspectives.
      In the context of reconstruction, the change in sequence of treatment may mitigate some of the effects of PMRT on the reconstructed breast: by irradiating the breast prior to mastectomy and reconstruction, the autologous flap itself is spared radiotherapy, potentially reducing fibrosis and fat necrosis. PRT is consistently reported to be both oncologically and surgically safe.
      • Monrigal E
      • Dauplat J
      • Gimbergues P
      • et al.
      Mastectomy with immediate breast reconstruction after neoadjuvant chemotherapy and radiation therapy. A new option for patients with operable invasive breast cancer. Results of a 20 years single institution study.
      • Zinzindohoue C
      • Bertrand P
      • Michel A
      • et al.
      A Prospective Study on Skin-Sparing Mastectomy for Immediate Breast Reconstruction with Latissimus Dorsi Flap After Neoadjuvant Chemotherapy and Radiotherapy in Invasive Breast Carcinoma.
      • Ho AL
      • Tyldesley S
      • Macadam SA
      • et al.
      Skin-sparing mastectomy and immediate autologous breast reconstruction in locally advanced breast cancer patients: a UBC perspective.
      • Pazos M
      • Corradini S
      • Schonecker S
      • et al.
      Neoadjuvant radiotherapy followed by mastectomy and immediate breast reconstruction: An alternative treatment option for locally advanced breast cancer.
      • Grinsell D
      • Pitcher M
      • Nielsen HHM
      • et al.
      Immediate autologous breast reconstruction after neoadjuvant chemoradiotherapy for breast cancer: initial results of the first 29 patients.
      • Paillocher N
      • Richard M
      • Classe JM
      • et al.
      Evaluation of mastectomy with immediate autologous latissimus dorsi breast reconstruction following neoadjuvant chemotherapy and radiation therapy: A single institution study of 111 cases of invasive breast carcinoma.
      Other potential benefits of PRT include reduced time to completion of treatment,
      • O' Halloran N
      • McVeigh T
      • Martin J
      • et al.
      Neoadjuvant chemoradiation and breast reconstruction: the potential for improved outcomes in the treatment of breast cancer.
      improved access to immediate breast reconstruction
      • O' Halloran N
      • McVeigh T
      • Martin J
      • et al.
      Neoadjuvant chemoradiation and breast reconstruction: the potential for improved outcomes in the treatment of breast cancer.
      ,
      • Boersma LJ
      • Lightowlers S
      • Offersen BV
      • et al.
      Where should we place radiotherapy: Before or after surgery?.
      and the ability to assess tumour response to radiotherapy which may prove to be a surrogate endpoint for local control, potentially improving the efficiency of knowledge-generating research and offering the opportunity for radiobiological studies.
      • Boersma LJ
      • Lightowlers S
      • Offersen BV
      • et al.
      Where should we place radiotherapy: Before or after surgery?.
      Operative concern with PRT were largely related to radiation related-vascular injury leading to poor healing and necrosis of skin flaps.
      • Monrigal E
      • Dauplat J
      • Gimbergues P
      • et al.
      Mastectomy with immediate breast reconstruction after neoadjuvant chemotherapy and radiation therapy. A new option for patients with operable invasive breast cancer. Results of a 20 years single institution study.
      ,
      • Riet FG
      • Fayard F
      • Arriagada R
      • et al.
      Preoperative radiotherapy in breast cancer patients: 32 years of follow-up.
      Outcomes pertaining to wound complications and skin necrosis rates from recent trials involving PRT, mastectomy and breast reconstruction have, however, been reassuring.
      • Paillocher N
      • Richard M
      • Classe JM
      • et al.
      Evaluation of mastectomy with immediate autologous latissimus dorsi breast reconstruction following neoadjuvant chemotherapy and radiation therapy: A single institution study of 111 cases of invasive breast carcinoma.
      ,
      • Giacalone PL
      • Rathat G
      • Daures JP
      • et al.
      New concept for immediate breast reconstruction for invasive cancers: feasibility, oncological safety and esthetic outcome of post-neoadjuvant therapy immediate breast reconstruction versus delayed breast reconstruction: a prospective pilot study.
      ,
      • Baltodano PA
      • Reinhardt ME
      • Flores JM
      • et al.
      Preoperative Radiotherapy Is Not Associated with Increased Post-mastectomy Short-term Morbidity: Analysis of 77,902 Patients.
      An additional challenge was to define the time line to enable resolution of acute inflammation, facilitate maximise tumour regression yet minimise fibrotic changes within the surgical field.
      Aesthetic outcome after PRT and reconstruction is reported to be good to excellent in the majority of studies.
      • Ho AL
      • Tyldesley S
      • Macadam SA
      • et al.
      Skin-sparing mastectomy and immediate autologous breast reconstruction in locally advanced breast cancer patients: a UBC perspective.
      ,
      • Pazos M
      • Corradini S
      • Schonecker S
      • et al.
      Neoadjuvant radiotherapy followed by mastectomy and immediate breast reconstruction: An alternative treatment option for locally advanced breast cancer.
      ,
      • Paillocher N
      • Richard M
      • Classe JM
      • et al.
      Evaluation of mastectomy with immediate autologous latissimus dorsi breast reconstruction following neoadjuvant chemotherapy and radiation therapy: A single institution study of 111 cases of invasive breast carcinoma.
      ,
      • Giacalone PL
      • Rathat G
      • Daures JP
      • et al.
      New concept for immediate breast reconstruction for invasive cancers: feasibility, oncological safety and esthetic outcome of post-neoadjuvant therapy immediate breast reconstruction versus delayed breast reconstruction: a prospective pilot study.
      However, heterogeneity between surgical techniques, methods of assessment, scales for scoring cosmesis and follow-up limit comparison between studies or a meta-analysis of results.
      The Pre-operative Radiotherapy And Deep Inferior Epigastric artery Perforator (DIEP) flAp study (PRADA study) [NCT02771938] was a prospective cohort study to assess the surgical safety and feasibility of PRT in women with locally advanced breast cancer undergoing neoadjuvant chemotherapy, mastectomy and deep inferior epigastric artery perforator (DIEP) flap reconstruction who would be recommended PMRT. The primary end-point was presence of an open breast wound at 4 weeks post-surgery.
      • Thiruchelvam PTR
      • Leff DR
      • Godden AR
      • et al.
      Primary radiotherapy and deep inferior epigastric perforator flap reconstruction for patients with breast cancer (PRADA): a multicentre, prospective, non-randomised, feasibility study.
      Secondary endpoints included aesthetic evaluation and patient satisfaction, and these are reported here.

      Methods

      The PRADA study recruited at two major London centres performing a high volume of autologous breast reconstructions. All patients that were due to undergo NACT, mastectomy with DIEP flap reconstruction (either following unsuccessful breast conservation surgery or upfront selection), and PMRT were offered the alternative sequence of radiotherapy before skin-sparing mastectomy and DIEP reconstruction. In these patients, radiotherapy was delivered to the breast (+/- regional nodes) 2-6 weeks after completing neoadjuvant chemotherapy and 4-6 weeks before surgery. The radiotherapy dosing schedule was either 40Gy in 15 fractions over 3 weeks or 42.72Gy in 16 fractions over 3.2 weeks. 33 patients were recruited to the PRADA study between 2016-18 and the primary outcome measure was presence an open wound at 4-weeks. All participants were invited to participate in 3D-SI at baseline, 3 and 12 months post-operatively to enable aesthetic evaluation of the outcome. Only one of the three sites had 3-Dimensional Surface Imaging (3D-SI) capability so, while all participants were invited to join the aesthetic outcome sub-study, only those who were able to travel to that site were included. At the same time points, participants also completed a BREAST-Q breast reconstruction questionnaire - a validated patient reported outcome measure (PROM) used to measure health related quality of life and patient satisfaction.
      • Pusic AL
      • Klassen AF
      • Scott AM
      • et al.
      Development of a new patient-reported outcome measure for breast surgery: the BREAST-Q.
      Results from a previous study of aesthetic outcome after DIEP flap reconstruction and PMRT at the Royal Marsden were used for comparison and will henceforth be referred to as the DIEP-PMRT cohort.
      • O'Connell RL
      • Di Micco R
      • Khabra K
      • et al.
      Comparison of Immediate versus Delayed DIEP Flap Reconstruction in Women Who Require Postmastectomy Radiotherapy.
      The 28 participants in the DIEP-PMRT cohort underwent mastectomy and DIEP reconstruction followed by PMRT between 2009 and 2014. A single 3D-SI and BREAST-Q were completed at a median follow up of 23 (IQR 17-38) months after treatment. Some women in the DIEP-PMRT cohort received a higher dose of radiotherapy than those in the PRADA group (Table 2). Propensity-matching was not undertaken as the follow-up period did not overlap.
      3D-SIs were acquired using VECTRA XT® capture system (Canfield Scientific, New Jersey, USA). Women were positioned with their hands on their hips and their elbows behind the mid-axillary line to optimise visualisation of the lateral aspect of the breast. The images were taken at the end-inspiratory pause during quiet breathing.
      3D-SIs from both cohorts were subject to panel evaluation using a scale developed through a Delphi consensus process specifically for breast reconstruction.
      • Godden AR
      • Wood SH
      • James SE
      • et al.
      A scoring system for 3D surface images of breast reconstruction developed using the Delphi consensus process.
      It consists of 5 sub-scales (symmetry, volume, shape, position of breast mound, and nipple-areola complex) in addition to a global scale. A 5-point Likert scale was used for each scale ranging from ‘very poor’ (1) to ‘excellent’ (5) (Table 3). Nine clinicians with at least 5 years’ experience at consultant level comprised the panel: three oncoplastic surgeons, three plastic surgeons, and three radiation oncologists. To reduce bias, panellists were blinded to surgeon, radiation oncologist, and patient identity, as well as to the treatment received. A standardised sequence of 7 views of each 3D-SI was shown to the panel (right and left lateral and oblique, anteroposterior, cranial, and caudal). Images were viewed in one sitting and panellists could ask for a patient sequence to be repeated if they required more time to give a score. Pre-treatment images were not scored. Discussion about scores was not permitted. The panel was not shown benchmark images.
      The BREAST-Q reconstruction module questionnaires were analysed using the Q-Score software. The resulting Q-score is from 0-100, with 100 being the best score. The results were compared with those from the DIEP-PMRT cohort. The minimal difference in the reconstruction BREAST-Q score which translates into clinical utility has been calculated at 4 points.
      • Voineskos SH
      • Klassen AF
      • Cano SJ
      • et al.
      Giving Meaning to Differences in BREAST-Q Scores: Minimal Important Difference for Breast Reconstruction Patients.

      Statistical Analysis

      IBM SPSS Statistics 24 was used to analyse the data. The mean global panel score from the 9 panellists was used for analysis. Simple descriptive statistics were used, either mean and standard deviation or median and inter-quartile range according to the distribution of the data. The Mann-Whitney U test was used to describe the significance of between-group differences for panel and Q-scores.

      Results

      Seventeen out of 33 women from the PRADA study participated in the aesthetic evaluation. 3D-SI was completed by 15 women at baseline, 15 at three months’ and 13 at 12-months’ follow-up. BREAST-Q was completed by 14 women at baseline, (pre-operative), 13 at 3 months and 12 at 12 months. Completed BREAST-Q questionnaires were available for 27 of the 28 participants in the DIEP-PMRT cohort and 3D-SI was available for all.
      Demographics and clinical data are reported in Table 1. Operation dates for the DIEP-PMRT cohort ranged from October 2009 to September 2014 and for the PRADA cohort from April 2016 to March 2018. Median follow-up was significantly shorter in the PRADA group compared to the DIEP-PMRT cohort at 12 (IQR 12-12) and 23 (IQR 17-38) and months respectively (p<0.01). Mean (range) age was significantly lower in the PRADA cohort compared to the DIEP-PMRT cohort 49 (range 36-60) and 57 (range 42-72) (p<0.01). BMI was similar between cohorts. Median time from radiotherapy to surgery for the whole PRADA cohort was 20 days in the PRADA cohort.
      Table 1Inclusion and exclusion criteria for the PRADA and DIEP-PMRT cohorts.
      Inclusion CriteriaExclusion Criteria
      PRADA Cohort
      • Thiruchelvam PTR
      • Leff DR
      • Godden AR
      • et al.
      Primary radiotherapy and deep inferior epigastric perforator flap reconstruction for patients with breast cancer (PRADA): a multicentre, prospective, non-randomised, feasibility study.


      (PRT – DIEP)
      >18 years

      Histopathological confirmation of breast cancer

      Require mastectomy for any reason

      Require adjuvant radiotherapy

      Suitable for DIEP flap reconstruction at the time of mastectomy
      Inability to give informed consent

      MDM unable to recommend radiotherapy based on pre-operative histopathological and imaging findings

      Severe chemotherapy toxicity affecting treatment plan schedule
      DIEP – PMRT cohort
      • O'Connell RL
      • Di Micco R
      • Khabra K
      • et al.
      Comparison of Immediate versus Delayed DIEP Flap Reconstruction in Women Who Require Postmastectomy Radiotherapy.
      >18 years

      Histopathological confirmation of breast cancer

      Mastectomy and immediate DIEP reconstruction

      PMRT

      Operated between 2009-2014 at the Royal Marsden Hospital

      Able to attend for 3D-SI and complete BREAST-Q
      Subsequent diagnosis of local recurrence, contralateral breast cancer, or metastatic disease

      Less than 1 year after the end of oncologic treatment

      Inability to answer the questionnaire or living outside the United Kingdom

      DIEP flap for chest wall resurfacing rather than breast reconstruction

      DIEP flap for non-breast cancer abnormality (e.g., sarcoma)

      DIEP flap for cosmetic failure of other reconstruction/breast conservation

      “Salvage” DIEP flap reconstruction i.e. failure of implant reconstruction to a flat chest wall and subsequent DIEP reconstruction.
      Table 2Demographics for the PRADA aesthetic cohort and the DIEP-PMRT cohort
      PRADA cohort n=17DIEP-PMRT cohort n=28Significance
      Age

      mean (range)
      49 (36-60)57 (42-74)P<0.001
      BMI

      mean (range)
      27 (21-36)27 (21-34)P=0.57
      Follow up in months

      median (IQR)
      12 (12-12)23 (17-38)P=0.01
      Axillary treatment (%)

      Surgery

      SLNB

      ALND

      Radiotherapy

      Axilla

      SCF

      IMC


      9 (47)

      8 (53)

      2

      11

      1


      9 (32)

      19 (68)


      P=0.29

      -

      Symmetrising surgery (%)4(24)6(21)P=0.869
      Radiotherapy regime (%)

      50Gy 25#

      40Gy 15#

      42.67Gy 16#

      Performed at a different centre


      0

      13 (76)

      4 (24)

      0


      7 (25)

      13 (46)

      2 (7)

      6 (21)


      P=0.09

      Table 3Likert scale used in the panel evaluation
      Excellent 5Good 4Moderate 3Poor 2Very Poor 1
      ShapeThe global shape of the reconstructed breast/sShape symmetry out of bra achievedShape of operated breast is pleasing but not symmetricalModerate difference in shape but does not detract from overall aesthetic resultModerate focal deficits detracting from overall aesthetic resultLarge focal deficits distorting contour significantly detracts from overall aesthetic result
      VolumeOverall volume symmetry between breastsEqual volume between breastsMinor difference in VolumeModerate difference in volume but does not detract from overall aesthetic resultVolume difference impacts overall aesthetic resultMajor volumes mismatch significantly detracts from overall aesthetic result
      Nipple PositionNipple position in relation to the ipsilateral breastExcellent symmetry between sides and nipple in an ideal position on reconstructed breast moundMinor adjustments required to achieve excellence in nipple positionNoticeably suboptimal but does not influence overall aesthetic resultsNipple position slightly impacts overall aesthetic resultNipple position significantly detracts from overall aesthetic result
      Position of Breast MoundIn relation to chest wall and other breastEqual to the other side and in an optimal position on chest wallMinor asymmetry of position or symmetrical but suboptimal positionAsymmetry of position or symmetrical but suboptimal position not detracting from overall aesthetic resultSlightly impacts overall aesthetic resultSignificantly detracts from overall aesthetic result
      SymmetryComparison between breastsOut of bra symmetry achievedMild asymmetryModerate asymmetry but does not detract from overall aesthetic resultModerate asymmetry detracting from overall aesthetic resultSignificant asymmetry detracting from overall aesthetic result
      GlobalTaking into consideration subscale evaluation what is your overall impression of the quality of the reconstructionExcellentGoodModeratePoorVery Poor

      Patient satisfaction

      The median (IQR) ‘satisfaction with breasts’ Q-score for the PRADA cohort was 48 (48-53), 73 (67-81) and 77 (72-87) at baseline, 3 and 12 months respectively, and 64 (54-71) in the DIEP-PMRT cohort at a median follow-up of 23 (IQR 17-38) months (Figure 1). The Q-score for the PRADA cohort at 12 months was significantly higher than for the DIEP-PMRT cohort (p = 0.01). The Q-scores for the other BREAST-Q domains are illustrated in Table 4.
      Figure 1
      Figure 1Box and whisker plot comparing the median Q-Score for the BREAST-Q reconstruction module for the PRADA cohort at baseline, 3 and 12 months and the DIEP-PMRT cohort (median follow up 23 months). Q-score of 100 is the maximum achievable.
      Table 4Summary of Q-score for the BREAST-Q Reconstruction module for the PRADA cohort at baseline, 3 and 12 months post-surgery and the DIEP-PMRT cohort (median follow up 23 months). Q-score of 100 is the maximum achievable.
      Measurement time-pointSatisfaction with breastsSatisfaction with outcomePsychosocial wellbeingPhysical wellbeing (chest)Physical wellbeing (abdomen)Sexual wellbeing
      Median (IQR)Median (IQR)Median (IQR)Median (IQR)Median (IQR)Median (IQR)
      PRADA cohort baseline n=14/1748 (48-53)-60 (53-79)77 (70-91)92 (83-100)48 (40-60)
      PRADA cohort at 3 months n=13/1773 (67-81)100 (75-100)79 (67-82)63 (58-78)70 (67-84)54 (49-67)
      PRADA cohort at 12 months n=12/1777 (72-87)100 (83-100)76 (62-92)83 (80-93)79 (70-100)57 (42-93)
      Historic control n=27/2864 (54-71)75 (67-100)70 (62-86)74 (66-85)89 (75-89)49 (44-66)

      Panel assessment of aesthetic outcome

      The median (IQR) global panel score for the PRADA cohort at 3 months was 3.9 out of 5 (3.8-4.4) and 4.3 out of 5 (3.9-4.6) at 12 months, the for the DIEP-PMRT cohort was 3.6 out of 5 (2.8-4) at 23 months as illustrated in Figure 2. The panel score for the PRADA cohort at 12 months was significantly higher than for the DIEP-PMRT cohort at 23 months follow-up (p = 0.003). Figure 3 shows example 3D-SIs of participants from the PRADA and DIEP-PMRT cohorts with close to median panel scores.
      Figure 2
      Figure 2Box and whisker plot comparing median panel scores for the PRADA group at 3 and 12 months post-operatively and the DIEP-PMRT cohort (median post-radiotherapy follow up 23 months). DIEP; deep inferior epigastric artery perforator flap, PRADA; pre-operative radiotherapy and DIEP flap reconstruction study, PMRT; post mastectomy radiotherapy.
      Figure 3
      Figure 33D-SIs to represent median panel score from both cohorts. A) 3D-SI from the PRADA cohort with a panel score of 4.3 and ‘satisfaction with breasts’ score of 85 (PRADA cohort median panel and BREAST-Q scores 4.3 and 77). B) 3D-SI from the DIEP-PMRT cohort with a panel score of 3.6 and ‘satisfaction with breasts’ score of 69 (DIEP-PMRT cohort median panel and BREAST-Q scores 3.6 and 64). Both participants had unilateral surgery with no symmetrisation.

      Discussion

      This is the first prospective study to report on aesthetic outcome using a validated scale after PRT and DIEP flap reconstruction. Good expert panel aesthetic scores were awarded to the PRADA cohort, with a median panel score of 4.3 out of a maximum of 5 points at 12 months’ follow-up. This was significantly better than the scores awarded to DIEP-PMRT cohort. However, as PRADA was a surgery feasibility study, it was not powered for this specific endpoint. The wider IQR observed in the DIEP-PMRT cohort may reflect the variability of results with PMRT, and potentially indicate more predictable results with PRT.
      There are caveats to the comparison, in that the follow-up period for the DIEP-PMRT cohort is almost double that of the PRADA cohort, therefore the effect of radiotherapy over time may not be fully appreciated. It is reported that two thirds of complications of PMRT occur within the first year and 80% within two years,
      • Lee SJ
      • Kwak YK
      • Park EY
      • et al.
      Complication analysis of breast cancer patients treated with mastectomy with IABR and PMRT Int.
      ,
      • S Sacotte R
      • Fine N
      • Kim JY
      • et al.
      Assessing long-term complications in patients undergoing immediate postmastectomy breast reconstruction and adjuvant radiation.
      so although major differences are unlikely to have been missed, longer-term follow up is required to examine degradation of aesthetic results over time in both cohorts to truly appreciate the potential differences between PRT and PMRT on DIEP flap reconstruction aesthetic outcomes. There were also differences in radiotherapy dose between groups with a proportion (although not statistically significant) in the DIEP-PMRT cohort receiving higher dose which may confound aesthetic outcomes.

      Patient satisfaction with breasts

      A 13-point difference in ‘satisfaction with breasts’ score was observed between the PRADA aesthetic cohort at 12 months and the DIEP-PMRT cohort at 23 months, and while this suggests better aesthetic outcome after PRT, we may not observe such a difference in a randomised study where the groups are more closely matched. Scores improved between 3 and 12 months, and one hypothesis is that post-operative discomfort or physical limitation, oedema and scarring improve over this time frame. An alternative hypothesis is that the women who did not provide a response to the questionnaire at 12 months were less satisfied. Two of the five women who did not respond at 12 months, did respond at 3 months. Their scores were below the group's median for both ‘satisfaction with breasts’ and ‘psychosocial wellbeing’. This reinforces the need for a larger, ideally randomised, trial.

      Panel assessment of aesthetics

      Ninety two percent of patients in the PRADA cohort received a good/excellent panel score (score of 4 or 5). Comparison with other PRT/reconstruction studies is challenging not only because of methodological differences between panel evaluations, but also numerous other differences between studies.
      In 2010, Giacalone et al reported aesthetic outcomes for 18 patients who received neoadjuvant chemoradiotherapy, skin-sparing mastectomy and immediate latissimus dorsi reconstruction and 54 patients who received mastectomy, adjuvant radiotherapy and delayed reconstruction at mean follow up of 4.7 years (without explicit reporting of the difference in follow-up between the two groups). 78% of the neoadjuvant chemoradiotherapy and immediate reconstruction group were awarded a good or excellent score by physicians versus 87% for the delayed reconstruction group.
      • Giacalone PL
      • Rathat G
      • Daures JP
      • et al.
      New concept for immediate breast reconstruction for invasive cancers: feasibility, oncological safety and esthetic outcome of post-neoadjuvant therapy immediate breast reconstruction versus delayed breast reconstruction: a prospective pilot study.
      The investigators employed the Gerber scale which includes 6 domains each with a maximum of 2-points (volume, shape, symmetry, ipsilateral and contralateral scars, and infra-mammary fold),
      • Gerber B
      • Krause A
      • Dieterich M
      • et al.
      The oncological safety of skin sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction: an extended follow-up study.
      and two physicians rated the outcome either in person at a follow-up visit or using photographs. Although certain domains are similar to those used in the PRADA study, the methodology is different on a number of levels (blinding, number of raters, views, 2D versus 3D photography). In addition, the comparison is drawn between a group with PMRT and delayed reconstruction limiting the relevance of the comparison.
      A German group, also using the Gerber scale, reported good or excellent aesthetic outcome in 6 of 9 patients who underwent PRT, mastectomy and immediate breast reconstruction.
      • Pazos M
      • Corradini S
      • Schonecker S
      • et al.
      Neoadjuvant radiotherapy followed by mastectomy and immediate breast reconstruction: An alternative treatment option for locally advanced breast cancer.
      This study had a small sample size and the type of reconstruction included implant-based reconstruction (with ADM, latissimus dorsi, or implant alone), DIEP flap, and transverse rectus abdominis myocutaneous flap (TRAM) which may lead to different results after radiotherapy due to more muscle fibrosis/atrophy. The median follow up was 30 months (again without explicit statement that it was equal for the two groups). The median time from radiotherapy to surgery was 47 days which is longer than for the PRADA cohort (20 days) with a wider range (26 - 162 versus 12 - 39 days). The radiotherapy dose was also higher than for PRADA (50.4Gy versus 40-42.72Gy).
      A Canadian group published a retrospective review in 2012 of 30 women who received PRT and autologous reconstruction and reported good or excellent results in two thirds.
      • Ho AL
      • Tyldesley S
      • Macadam SA
      • et al.
      Skin-sparing mastectomy and immediate autologous breast reconstruction in locally advanced breast cancer patients: a UBC perspective.
      A 4-point scale described by Kroll was used for shape and symmetry, where 3-points equated to a good score and 4- an excellent score.
      • Kroll SS
      • Schusterman MA
      • Reece GP
      • et al.
      Breast reconstruction with myocutaneous flaps in previously irradiated patients.
      The senior author of the paper evaluated the outcome leaving the results open to bias. The median follow-up was longer than PRADA (3.5 years), the types of reconstruction used were latissimus dorsi, TRAM, or a combined method rather than DIEP reconstruction, the median time from radiotherapy to surgery was longer at 6.9 weeks (range 2.7-12.9), and the dose of radiotherapy was higher for most participants, 50Gy for 60% and hypo-fractionated for 40% (2.5Gy per fraction over 3.5 weeks).
      Heterogeneity in study populations may reflect wide variations in clinical practice and changing trends in breast reconstruction. Internationally, over the past two decades, uptake of immediate breast reconstruction has increased (two-fold in the UK between 1996-2012).
      • Leff DR
      • Bottle A
      • Mayer E
      • et al.
      Trends in Immediate Postmastectomy Breast Reconstruction in the United Kingdom.
      Implant-based breast reconstruction remains the most popular reconstruction method (2015 data), there has been a decline in the popularity of latissimus dorsi based reconstruction and an increase in DIEP flap reconstruction, most notably at specialist and academic centres.
      • Leff DR
      • Bottle A
      • Mayer E
      • et al.
      Trends in Immediate Postmastectomy Breast Reconstruction in the United Kingdom.
      . At one of the institutions involved in the PRADA study, rates of LD-assisted reconstruction fell from 54% to under 1% of total immediate breast reconstruction from 2004-2013. Conversely DIEP flap reconstruction rose from 1% to 38% over the same period.
      • Leff DR
      • Bottle A
      • Mayer E
      • et al.
      Trends in Immediate Postmastectomy Breast Reconstruction in the United Kingdom.

      Patient-reported outcome measures (PROMs)

      The PRADA cohort ‘satisfaction with breasts’ Q scores at 12 months follow-up was 77 [IQR 72-87], 13 points superior to those of the DIEP-PMRT cohort at 64 [IQR 54-71]. Disparity in follow-up may be a confounder. Participants in the PRADA cohort may also have had a perception of improved reconstructive quality owing to the theoretical benefits of ‘sparing’ the reconstruction the effects of radiotherapy. Complications associated with radiotherapy and breast reconstruction in the adjuvant or neoadjuvant setting can develop over a number of years, therefore longer term PROMs comparison between PRT and PMRT groups is required.
      • Clemens MW
      • Kronowitz SJ.
      Current perspectives on radiation therapy in autologous and prosthetic breast reconstruction.
      The literature on aesthetic evaluation of reconstruction followed by PMRT has many limitations, with heterogenous populations and methods. However, it would appear that the ‘satisfaction with breasts’ Q-score for the PRADA population is also higher than in other studies of PMRT. Q-scores for irradiated implant-based reconstruction range from 40 to 58,
      • Cordeiro PG
      • Albornoz CR
      • McCormick B
      • et al.
      What Is the Optimum Timing of Postmastectomy Radiotherapy in Two-Stage Prosthetic Reconstruction: Radiation to the Tissue Expander or Permanent Implant?.
      • Albornoz CR
      • Matros E
      • McCarthy CM
      • et al.
      Implant breast reconstruction and radiation: a multicenter analysis of long-term health-related quality of life and satisfaction.
      • Alshammari SM
      • Aldossary MY
      • Almutairi K
      • et al.
      Patient-reported outcomes after breast reconstructive surgery: A prospective cross-sectional study.
      and for irradiated autologous reconstructions from 44 to 66.
      • He S
      • Yin J
      • Robb GL
      • et al.
      Considering the Optimal Timing of Breast Reconstruction With Abdominal Flaps With Adjuvant Irradiation in 370 Consecutive Pedicled Transverse Rectus Abdominis Myocutaneous Flap and Free Deep Inferior Epigastric Perforator Flap Performed in a Chinese Oncology Center: Is There a Significant Difference Between Immediate and Delayed?.
      ,
      • Alshammari SM
      • Aldossary MY
      • Almutairi K
      • et al.
      Patient-reported outcomes after breast reconstructive surgery: A prospective cross-sectional study.
      A study comparing ‘satisfaction with breasts’ in all types of breast cancer surgery (conservation, mastectomy only, mastectomy and reconstruction (implant and autologous) reported a Q-score of 71 for autologous reconstruction of which only 21% were irradiated.
      • Lagendijk M
      • van Egdom LSE
      • van Veen FEE
      • et al.
      Patient-Reported Outcome Measures May Add Value in Breast Cancer Surgery.
      A Chinese study compared Q-scores after autologous reconstruction (TRAM or DIEP) with (n=86) and without (n=246) PMRT at >1-year follow-up. At 12 months the ‘satisfaction with breasts’ and ‘psychosocial wellbeing’ Q-scores for the unirradiated cohort were 68 and 76 respectively
      • He S
      • Yin J
      • Robb GL
      • et al.
      Considering the Optimal Timing of Breast Reconstruction With Abdominal Flaps With Adjuvant Irradiation in 370 Consecutive Pedicled Transverse Rectus Abdominis Myocutaneous Flap and Free Deep Inferior Epigastric Perforator Flap Performed in a Chinese Oncology Center: Is There a Significant Difference Between Immediate and Delayed?.
      which are comparable to the PRADA cohort at one year (77 and 76 respectively). Lagendijk et al report Q-scores for psychological, physical, and sexual well-being for 83 autologous reconstruction cases (78, 76 and 62 respectively) of which 22% were irradiated,
      • Lagendijk M
      • van Egdom LSE
      • van Veen FEE
      • et al.
      Patient-Reported Outcome Measures May Add Value in Breast Cancer Surgery.
      which is similar to the PRADA cohort score for the respective domains (76, 83, 57). In contrast, a number of studies have failed to show a difference in patient-reported satisfaction for autologous reconstruction with or without PMRT.
      • He S
      • Yin J
      • Robb GL
      • et al.
      Considering the Optimal Timing of Breast Reconstruction With Abdominal Flaps With Adjuvant Irradiation in 370 Consecutive Pedicled Transverse Rectus Abdominis Myocutaneous Flap and Free Deep Inferior Epigastric Perforator Flap Performed in a Chinese Oncology Center: Is There a Significant Difference Between Immediate and Delayed?.
      ,
      • Cooke AL
      • Lambert P
      • Diaz-Abele J
      • et al.
      Radiation Therapy Versus No Radiation Therapy to the Neo-breast Following Skin-Sparing Mastectomy and Immediate Autologous Free Flap Reconstruction for Breast Cancer: Patient-Reported and Surgical Outcomes at 1 Year-A Mastectomy Reconstruction Outcomes Consortium (MROC) Substudy.
      While mindful of the aforementioned caveats limiting between-study comparisons, these observations may suggest that patients could be just as satisfied with their aesthetic outcome with PRT as they are in the absence of radiotherapy.
      Studies reporting PROMs after PRT are scarce. Giacalone et al used the Gerber scale and reported excellent or good aesthetic outcome in 89% of participants.
      • Giacalone PL
      • Rathat G
      • Daures JP
      • et al.
      New concept for immediate breast reconstruction for invasive cancers: feasibility, oncological safety and esthetic outcome of post-neoadjuvant therapy immediate breast reconstruction versus delayed breast reconstruction: a prospective pilot study.
      In a retrospective series of 111 patients who received PRT with latissimus dorsi reconstruction (+/- implant) an average patient satisfaction score of 17 out of 20 (85%) was reported at a median follow-up of 31months.
      • Paillocher N
      • Richard M
      • Classe JM
      • et al.
      Evaluation of mastectomy with immediate autologous latissimus dorsi breast reconstruction following neoadjuvant chemotherapy and radiation therapy: A single institution study of 111 cases of invasive breast carcinoma.
      The questionnaire used was not validated so interpretation of results is challenging, but nonetheless encouraging. Other studies of neoadjuvant radiotherapy and breast reconstruction either do not evaluate aesthetic outcome at all,
      • Monrigal E
      • Dauplat J
      • Gimbergues P
      • et al.
      Mastectomy with immediate breast reconstruction after neoadjuvant chemotherapy and radiation therapy. A new option for patients with operable invasive breast cancer. Results of a 20 years single institution study.
      ,
      • Zinzindohoue C
      • Bertrand P
      • Michel A
      • et al.
      A Prospective Study on Skin-Sparing Mastectomy for Immediate Breast Reconstruction with Latissimus Dorsi Flap After Neoadjuvant Chemotherapy and Radiotherapy in Invasive Breast Carcinoma.
      ,
      • Barrou J
      • Bannier M
      • Cohen M
      • et al.
      Pathological complete response in invasive breast cancer treated by skin sparing mastectomy and immediate reconstruction following neoadjuvant chemotherapy and radiation therapy: Comparison between immunohistochemical subtypes.
      or do not describe their methods.
      • Grinsell D
      • Pitcher M
      • Nielsen HHM
      • et al.
      Immediate autologous breast reconstruction after neoadjuvant chemoradiotherapy for breast cancer: initial results of the first 29 patients.
      Given that all of the PRADA patients had locally advanced breast cancer and received radiotherapy both of which have a negative impact on patient satisfaction, these early results from the feasibility study are encouraging.
      • Gnanajothy R
      • Correll JA
      • Peterson LL.
      Psychosocial well-being assessment in women with breast cancer.
      ,
      • Jensen RE
      • Potosky AL
      • Moinpour CM
      • et al.
      United States Population-Based Estimates of Patient-Reported Outcomes Measurement Information System Symptom and Functional Status Reference Values for Individuals With Cancer.
      ,
      • Greimel E
      • Thiel I
      • Peintinger F
      • et al.
      Prospective assessment of quality of life of female cancer patients.
      Within the limitations of this feasibility study, the PRADA treatment sequencing gives similar breast aesthetic outcomes, and warrants further large-scale, multi-centre evaluation in a randomised trial.

      Conclusion

      The PRADA cohort represents one of the first prospective cohorts of PRT and DIEP flap reconstruction using validated aesthetic evaluation measures. Aesthetic outcome is reported as good or excellent in 93% of cases using a bespoke panel assessment with robust methodology. Patient satisfaction at one year is encouraging and superior to DIEP and PMRT at 23 months. Heterogeneity in study design and methodology precludes reliable comparisons with published literature.

      Compliance with Ethical Standards

      There are no conflicts of interest.
      All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standard. The protocol was reviewed and passed by London-Riverside NRES committee
      • Paillocher N
      • Richard M
      • Classe JM
      • et al.
      Evaluation of mastectomy with immediate autologous latissimus dorsi breast reconstruction following neoadjuvant chemotherapy and radiation therapy: A single institution study of 111 cases of invasive breast carcinoma.
      /LO/0010. The study is registered on a publicly accessible database, clinicaltrial.gov, NCT02304614

      Acknowledgements

      This paper represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This work was supported by the NIHR Imperial Biomedical Research Centre. We would like to formally acknowledge the contributions of the participants, medical photographer Dennis Underwood, Sue Boyle and the members of the expert panel including Mr S H Wood, Mr S E James, Mr KWD Ramsey, Dr N Somaiah and Dr S Cleator.

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