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