postmastectomy radiotherapy after neo adjuvant chemotherapy in breast cancer

JOURNAL CLUB

Dr Bharti DevnaniModerator- Dr KP Haresh Date: 09-04-2016

Semin RadiatOncol26:51-58 2016

PMRT IN UPFRONT SETTING- EVIDENCE

Perez and Brady, Textbook of Radiation Oncology

PMRT IMPROVES OS - EBCTCG META-ANALYSIS

EBCTCG meta-analysis. Lancet 2005

PMRT IN NODE POSITIVE PATIENT

EBCTCG Meta-analysis Lancet 2014

PMRT IN NODE NEGATIVE PATIENT

EBCTCG Meta-analysis Lancet 2014

INDICATIONS OF PMRT ARE EXPANDING…..

Isolated local recurrence

Breast cancer mortality

Radiation is an important treatment post MRM

Standard indications of PMRT T4 Node positive disease Margin positive T3N0 with high risk features

No benefit in pN0 disease

Decision of PMRT is mainly based on histo-pathological findings

ROLE OF NACT

Targeting systemic and locoregional disease

Downstaging of disease

Breast conservation

In vivo assessment of sensitivity of chemotherapy

To tailor and limit subsequent locoregional treatment

Increasing pCR 10-15 % with anthracyclines 25-30% with anthracyclines/Taxane 40-50 % with chemo + transtuzumab in Her-

2+ 50-60% with chemo and 2 anti Her-2 agents

Decrease in rates of axillary positivity 30 % with anthracyclines Upto 40% with anthracyclines/Taxane > 50% with chemo and 2 anti Her-2 agents

NACT- ASSOCIATION OF PCR WITH EFS & OS

Cortazer et al. Lancet 2014; 384: 164–72

NACT COMPLICATES DECISION MAKING OF PMRT

Jungle of risk factors

Response to

systemic treatment

Biological features

pT0/pN0pN0/residual

BrpT+/pN+

CLINICALAge

T sizeN stageStage

How to tailor the treatment decision of

LRRT based on above risk factors ??

Semin RadiatOncol26:51-58 C 2016 Semin RadiatOncol26:51-58 2016

Department of Radiation Oncology, The Ohio State University, Columbus, OH.

OUTLINEPublished literature from MDACC Risk factors of LRF Impact of PMRT on std risk features post

NACT

Grey areaso Young ageo Stage II diseaseo pCR- ypN0

Ongoing trials and future perspectives

RETROSPECTIVE DATA FROM MDACC

MDACC PATIENTS POOL

Huang et al. IJROBP 2005;62:351-7

CLINICO-PATHOLOGICAL FACTORS PREDICTIVE OF LRF & IMPACT OF PMRT

Huang et al. IJROBP 2005;62:351-7

No RT group

RT group

T3-T4 56% 84%N2-N3 20% 43%N+ 52% 72%

Patient characteristics

LRR rate RT v/s no RT

22% vs 11%

SUBSET ANALYSISLRR who initially had stage III or IV & achieved pCR

33% vs 3%

Huang et al. IJROBP 2005;62:351-7

CAUSE SPECIFIC SURVIVALCSS for stage III and

IVCSS for > 4 nodes

positive

RISK FACTORS OF LRR

n =106

10years LRR irradiated v/s non irradiated --5% v/s 10%

McGuire et al. IJROBP 2007;68:1004-9

IMPORTANCE OF CLINICAL STAGE: PATIENTS WITH PCR

Not just the residual disease but the clinical extent of disease before treatment is also important

No RT-0/20 RT-0/10

No LRR events

Clinical Stage II disease Clinical Stage III disease

93 %

67 %

S

IMPORTANCE OF AGE <35 YEARS

Garg et al. IJROBP 2007;68:1478-83

Nagar et al. IJROBP 2011;81:782-7

4% vs 24% p<0.001

Nagar et al. IJROBP 2011;81:782-7

ypN+ ypN0

p <0.001 2% vs 14%p <0.06

RECOMMENDATION BASED ON MDACC STUDIESo Stage III diseaseo cN2-N3 involvemento Residual pathologically involved nodes(ypN

+)o CT3N0 pN+ disease post NACT

Role of PMRT for cT3N0 who remain yPN0 post NACT remains unclear

LIMITATIONS OF MDACC STUDIES Retrospective

Single institutional data

Non-randomised (Bias)

Follow up is relatively modest

PMRT IN WOMEN WITH PATHOLOGICAL NEGATIVE LYMPH NODE

NSABP B-18/B-27- COMBINED ANALYSIS

10 YR CUMULATIVE LRR RATES IN POST MRM PATIENTS <5 CM

Mamouns et al. J Clin Oncol 2012; 30:3960-3966

10 YR CUMULATIVE LRR RATES IN POST MRM PATIENTS >5 CM

NOMOGRAM FOR PREDICTION OF 10 YRS RATE OF LRR- POST MRM

10-year LRR-FS, 96.2% vs 86.8% p=0.18

n=13478 & 56

10-year OS, 77.2% vs 87.7% p=0.15

Scodan et al. IJROBP 2012;82:1-7

Omission of PMRT was notdetrimental in Stage II ,IIIpatients with negative lymph nodes after NAC and mastectomy

Shim et al . IJROBP 2013;88:65-72

Annals of Oncology 00: 1–10, 2016

Benefit of PMRT in cN1 patients irrespective of thepathologic lymph node response to NAC

NSABP B-51 TRIALn=1636

ALLIANCE TRIAL Can RT alone provide sufficient regional

control for patients with ypN + disease after NAC

Prognostic value is greatest in

aggressive tumor subtype

Triple Neg

HR neg Her-2 +

Cortazer et al. Lancet 2014; 384: 164–72

Yang et al. Ann Surg Oncol 2015 22:495–501

Poor responders to NAC with TN breast cancer represent a populationat high risk for LRR, and maximal locoregional therapy should be considered for these patients

Fowble et al. IJROBP 2012;83: 494-503

CONCLUSION PMRT after NACT is debatable. Based on retrospective data PMRT –post

NACT should be given in Clinical stage III (especially N2-N3) Residual disease (++ if yp+) High risk factors like young age, triple

negative Stage II and T3 N0……still grey area…

personalized decision Prospective randomized trials are required

IRCH PROTOCOL All patients planned for NACT (Clinical stage

decided by combined team and documented in file clearly)

All BCS patients to receive WBRT+Boost.

Decision for Adjuvant therapy based on initial clinical staging and decision

Pathological CR not to guide radiation therapy!!!

FUTURE PERSPECTIVESIntensification of treatment in poor respondersConcurrent chemotherapyAltered fractionationRadiosensitizers like PARP inhibitors (SWOG

1509)

Need of comprehensive nodal irradiation (in TN & Her 2 +)

S1509, “A Phase II Study of Veliparib Administered Concurrently with Radiotherapy for Inflammatory or High-Risk Triple-Negative Breast Cancer to A Phase II Randomized, Double-Blinded, Placebo-Controlled Trial of Veliparib Administered Concurrently with Radiotherapy for Inflammatory or High-Risk Triple-Negative Breast Cancer.” Dr. Jagsi.