Is Radiotherapy of Reconstructed Breasts Safe (can a good cosmetic outcome from reconstruction be
preserved if radiotherapy is given)DR Susan Cleator MD PhD
Breast/ Colorectal/ Chemotherapy/ Radiotherapy
Imperial NHS Trust
Breast Cancer Research and Treatment: The 2016 Assisi Think Tank Meeting on breast cancer: white paperCynthia Aristei, Charlotte Coles et al
• Three issues were identified as needing further investigation:
• (1) Regional lymph node treatment in early-stage breast cancer
• (2) Combined post-mastectomy RT and breast reconstruction
• (3) RT in patients treated with primary systemic therapy
Indications for Mastectomy
• Risk reducing
• Extensive DCIS/ in situ component
• High risk invasive cancers
• Patient choice
Many will require radiotherapy:Formally: cancers ≥ 5cm
≥ 3 or 4 involved lymph nodessingle LN mass ≥3cm
Increasingly: N1 disease
high risk T2N0 medial cancersif axillary RT given en lieu of ANC
- nodal count unclear- may as well irradiate CW
In the future: ? less RT
-if RT adapted to response to neoadjuvant chemotherapy
-if molecular profiling applied
and PMRT
• Risk of cosmetic impact on reconstruction requiring multiple operations and impact on Q of L
• Catastrophic effect on reconstruction - pain/ reduced function
• Delayed healing of complex reconstruction can result in delays in delivering post op RT
• Radiotherapy is a barrier to immediate reconstruction in many centres
Select patients carefully for post-mastectomy/ immediate reconstruction RT: potential difficulties
with treatment
• Many of the trials were undertaken decades ago
• Management of axilla was often suboptimal
• Contemporary series suggest risk of LR low if 1-3 LN positive
• Contemporary series suggest risk of LR low if T3N0
• Many higher risk patients undergo neoadjuvant therapy
• Should radiotherapy recommendations be tailored to response?
• Awaiting results from SUPREMO study
• Post mastectomy, RT vs no RT, intermediate risk cases
• This will give us an event rate in absence of radiotherapy
Select patients carefully for post-mastectomy RT: challenges interpreting the data
UK Consensus
ASCO guidance 2016
• Consider for T1-2 tumors with N1 disease at ALND
• PMRT indicated for stage I or II cancers who have received NACT and remain node positive
• For NACT cases with clinically negative nodes or who have pCR in the lymph nodes, there is currently insufficient evidence to recommend whether PMRT should be administered or routinely omitted
• In mastectomy patients who have not undergone AND with 1-2 +ve sentinel nodes, PMRT should be considered only if there is already sufficient information to justify its use without needing to know that additional axillary nodes are involved
ASCO guidance 2016
• NSABP:
• Mamounas E et al, JCO, 2012• 3,000 women enrolled into NSABP B-18 and NSABP B-27
• BCS – RT
• Mx, no RT
• risk of LRR post Mx was considerable (>10%) for most subsets of patients with ypN1 disease
• chest wall recurrences post mx - were infrequent in patients who achieved breast pCR (one local recurrence in 94 patients)
• MDACC:
• McGuireS et al, Int J Radiot Oncol Biol Phy 2007:• for those who initially presented with stage III disease, LRR at 10 years 33.3% no RT vs 7.3% with
radiotherapy (P =0.04)
• however, similar locoregional recurrence rates were seen with or without radiotherapy in the group that presented with clinical stage I or II disease before chemotherapy
• Patients achieving pCR seemed to benefit from RT
Post neoadjuvant chemotherapy RT data
• On going in US: NSABP B51/RTOG (Radiation Therapy Oncology Group) 1304 phase III clinical trial (NCT01872975)
• Eligibility • patients who have a pCR in the lymph nodes
• clinical stage N2 to 3 disease, or stage IIIB or C disease are not eligible
• After mastectomy• patients are randomly assigned to no radiotherapy vs chest wall and
regional nodal radiotherapy
Ongoing Trial – Post neoadjuvant chemo and mastectomy RT in node positive cases that become node negative post chemotherapy
• Skin envelope (and its contents)• Most mastectomies are skin-sparing
• ? bolus
• Nodes• Scf
• Axilla
• Internal mammary chain (may actually treat 1.3 reconstructions if bilateral reconstruction)
What do we actually treat?
Types of Reconstruction
• Implant• Implant only
• Expandable
• Magni-site
• LD and implant
• Autologous
• Abdominal fat (DIEP)
• Inner thigh fat (TUG)
• Buttock (SGAP)
• LD +/- implant
• TRAM
Potential sequences
Mastectomy
Immediate reconstruction
Radiotherapy to reconstruction
Mastectomy
Radiotherapy to chest wall
Delayed reconstruction
Radiotherapy
Mastectomy
Immediate reconstruction
• No flat chest• Skin can be conserved• One op (!)• Implant only reconstruction
permissible (usually temporizing)
PROS • Avoid radiotherapy to reconstruction
• Smaller initial procedure• Minimize delay to
chemo/ RT
• No flat chest• Skin can be conserved • Avoid RT to reconstruction• Avoid delays to completion of
Oncological treatment
CONS• Risk of delay in radiotherapy
+/- chemo• RT to reconstruction
+/- chemo
+/- chemo +/- chemo chemo
• Flat chest• Can’t preserve skin • Complex reconstruction needed
• Less data on op complications• Loss of prognostic information
+/- chemo
• Fat necrosis – limited/ extensive
• Fibrosis (hardening/ shrinkage/ distortion/ swelling) of autologous skin
• Reduced patient satisfaction/ Q of L
• Loss of capacity to gain/lose weight in line with contralateral breast (DIEP)
• These can all happen in the absence of radiotherapy
• Radiotherapy can alleviate keloid scars
Potential radiotherapy induced complications – long term, autologous reconstruction
• Implants (capsule formation)• fibroproliferative interaction between irradiated implant surface and
surrounding tissue
• Less if implant contained within a sling of muscle (???matrix)
• macrophages and lymphocytes infiltrate around implant
• large amount of elastin content in implant capsule
• Autologous (fat necrosis)• Compromised vasculature
Mechanism of Complications
How can the impact of radiotherapy be measured?
TRAM +/-RT
Implant +/-RT
SUPREMON=…..
LD (+implant) +/-RT
DIEP +/-RT
• ? compare reconstruction type A versus reconstruction type A +RT in a single patient (e.g in same pt undergoing risk reducing contralateral surgery):• surgery to breast and nodes for a large cancer requiring RT may differ from surgery to small cancer not requiring RT?
• Metrics not simple:• ‘4D’ photos
• ‘compressibility’
• grading of capsule (Baker; clinical, 4 levels, simple)
• revision rates
• patient assessment (PROMS) – most important, least ‘objective’, but validated tools exist
• Other factors: BMI, breast size, smoking
Measuring Outcome
• Prospective Longitudinal Study of Cosmetic Outcome in Immediate Latissimus Dorsi Breast Reconstruction and Influence of Radiotherapy
• Annals of Surgical Oncology, 2008 (Thomson H et al/ Winter Z)
• Immediate LD reconstruction, 2000-2007, median F/U 2.7 years
• RT adversely affected outcomes by photo and BRA• worse if implant
• No statistically significant difference in patient reported outcomes, BIS• Outcomes deteriorated over time
• more so in RT group
Assessment must be prospective and protracted
53 implant assisted LD 20 Autologous LD
RT 18 (33%) RT 13 (65%)
Assessments:• Photographic: shape, size, cleavage, scarring, skin colour• BRA (designed for BCS, geometrical measurements)• Patient-reported cosmetic outcome questionnaire (novel)• Body image scale (Hopwood)
• Systemic review of 34 papers that include HR QoL measures in breast construction (Winters Z et al Annals Surgery, 2010)• Poor methodology
• Under-powered
• 6 included pts who had received RT
• 1 prospective (Brandberg Y et al. Plastic and Reconstr Surgery, 2000: RT no impact in autologous reconstructions – 28 pts out of 75 received RT, questionnaires at 6 and 12 months)
• Since, 2 breast reconstruction-specific PROMS assess HRQL• EORTC BRR QLQ-BRR26
• BREAST Q
PROMS
Prospective Study
• 2007-2013
• multicentre prospective longitudinal cohort
• Immediate LD reconstruction +/- implant, +/- RT
• 3 year follow-up
• Radiotherapy adversely affected social functioning at 2 years
78 implant assisted LD 104 Autologous LD
RT 17 (28%) RT 46 (44%)
PRO Assessments:• EORTC Quality of Life Core Questionnaires
• quality of life core-questionnaire (QLQ-C30)• breast cancer module (QLQ-BR23)
• Functional Assessment of Cancer Therapy – Breast (FACT-B) • Hospital Anxiety and Depression Scale (HADS)
Patient-reported outcomes and their predictors at 2- and 3-year follow-up after immediate latissimus dorsi breastreconstruction and adjuvant treatment. BRJ, 2016, Winters Z/ Afzal M
e.g:
• Rogers and Allen et al, 2002
• 5-point scoring of photos for 1) symmetry 2) aesthetic proportion and 3) appearance of upper pole breast, of 20 DIEP reconstructions, 10 of which were irradiated
• All 3 measurements scored worse in irradiated arm (stat sig)
• BUT…
• Only 10 patients
• Was surgery really equivalent (e.g. wrt axillary surgery)
• In short there are few good studies
• Objective measures of outcome usually divergent from PROMS data
Some but not all studies ‘suggestive’ of adverse outcome on autologous reconstruction
• Capsular contracture more common if RT delivered post implant only reconstruction• Gui et al, 2005 –
• 62 patients implant alone, 72 implant-assisted LD. 44 of 134 total breasts received RT.
• Capsule formation in 13/92 (14.1%) reconstructed breasts with no RT and in 17/44 (38.6%) reconstructed breasts with RT mean photo score 8 (95% CI 8, 8.5) in capsule group (worse) versus no capsule group 6.5 (95% CI 5, 7.5), p<0.001
• more than 60% of patients do not get capsules despite RT at four years…… ’implant-assisted tissue expansion techniques …………… is a viable breast reconstructive option in selected cases’
Implants and Radiotherapy
• Avoid implant only reconstruction if subsequent RT planned if alternative options are available and or acceptable
• Radiotherapy probably has potential to adversely affect outcome from autologous reconstruction (as it does to natural breast), although this is very poorly documented in the scientific literature
• An excellent result (as judged by patient and/ or doctor) still possible
• Professionals can’t always tell if radiotherapy has been delivered to a autologous reconstruction
Advice to patients?
• Or Having Expedited Radiotherapy prior to Mastectomy (and Reconstruction) – Equivalent or Superior?
• A two-centre non-randomised intervention trial investigating whether reversing the order of mastectomy (+axillary nodal clearance) with immediate DIEP flap reconstruction and adjuvant radiotherapy after neoadjuvant chemotherapy is safe
• Rationale: • Potentially improve cosmetic outcome without increasing post-op complications• Remove a barrier to immediate reconstruction• Safe in other surgical settings – head and neck/ abdominoperineal resection• Improve timeliness of radiotherapy• ?? Improved Oncological outcomes??
PRADA
Primary Radiotherapy And DIEP flAp reconstruction
N=6 selected post-operatively N=5 selected pre-operatively
• Requiring completion mastectomy after completion of ‘neoadjuvant chemotherapy’
• Indication for radiotherapy
• Requiring mastectomy after completion of neoadjuvant chemotherapy
• Indication for radiotherapy
N=13 recruited, N=11 complete surgical dataset
PRADA
Primary Radiotherapy And DIEP flAp reconstruction
• Primary Endpoint • Presence of open breast wound at 4 weeks after mastectomy & DIEP flap
reconstruction (Open wound defined as wound requiring a dressing />1cm)
• Secondary Endpoints • Presence of an open breast wound at 8 and 12 weeks • DIEP flap loss rate • Difference in volume and symmetry between the reconstructed and
non- reconstructed breast using 3D- surface imaging at 3 months and 12 months after surgery
• Patient satisfaction (BREAST- Q reconstruction module) 3 months/ 12 months• Difference in breast compressibility using applanation tonometry at 3 months/ 12
months
• Translational arm - Dr Navita Somaiah
PRADA
Primary Radiotherapy And DIEP flAp reconstruction
• Patients will be treated according to departmental protocol, 40Gy/ 15 fraction/ 3 weeks, 50Gy/25 fractions/5 weeks or 42.72Gy/16#/3.2 weeks
• Bolus as per local policy
• Patients will proceed to surgery at 2-6 weeks following completion of radiotherapy
• IMN irradiation permitted
PRADA
Primary Radiotherapy And DIEP flAp reconstruction
Challenges:
• Deciding on nodal radiotherapy prior to receiving histopathology
• ? PET on all to detect internal mammary involvement pre-op
PRADA
Primary Radiotherapy And DIEP flAp reconstruction
• n=1 revision of microvascular anastomosis - FRIABLE ARTERY - DIFFICULT ANASTOMOSIS
• n=1 unplanned return to theatre (80 hours post-op – haematoma)
• n=1 delay to RT delivery (i.e. >6/52 after NACT)
• n=1 clinical fat necrosis – 2cm (awaiting excision)
• NO DIEP flap failure
• NO wound dehiscence (4, 8 & 12 weeks)
• NO Mx skin flap necrosis (4, 8 & 12 weeks)
N=6 selected post-operatively
N=13 recruited
PRADA –PERI & POST-OPERATIVE COMPLICATIONS
• Median follow up = 16 months (8-25)
• No loco-regional recurrences
• N=3 distant relapse
• N=1 occipital metastases
• N=1 lung & liver metastases
• N=1 lung & spinal metastases
• N=2 breast cancer related deaths
• diagnosis – path CR, lung, pleural and liver metastases
RESULTS: PRELIMINARY ONCOLOGICAL OUTCOMES
• Extend current service evaluation of small numbers (Imperial, RMH)
• Randomised Control Trial (Pre-MxRecon DXT vs. Post-MxReconDXT)
• Improve the evaluation of cosmesis:
• 3D photography
• Panel assessment
• PROMS
• Extend follow up oncological outcome measures:
• LR
• DM
• Death from BC
RESULTS: PROPOSED Future work