EXTENDED FIELD IRRADIATION

FOR ADVANCED BREAST CANCER

PATIENTS, WHEN AND HOW?

CHEN JIA-YI

DEPARTMENT OF RADIATION ONCOLOGY

RUI-JIN HOSPITAL, SCHOOL OF MEDICINE,

SHANGHAI JIAO-TONG UNIVERSITY

GBCC 2018

CONCERNS AND CONTROVERSIES

Decision of regional nodes irradiation (RNI)

• In high risk patients after axillary dissection

• In node positive patients undergoing sentinel biopsy without dissection

Indication of post-surgical radiation after NAC

• In patients with initial stage II-III diseases receiving neo-adjuvant systemic therapy

Neo-adjuvant RT advances

Synergy of Radiation therapy and immunotherapy

3EBCTCG 2014

EBCTCG 2014

RT AFTER MASTECTOMY AND ALND (ALN4+)

RT: significant benefit

EBCTCG 2014

RT AFTER MASTECTOMY AND ALND (ALN 1-3+)

RT: significant benefit

4A : 1C

1.5B : 1C

RNI IN HIGH RISK PATIENTS AFTER ALND

French Trial EORTC 22922/10925 MA.20

Year of enroll 1991-1997 1996-2004 2000-2007

Sample size 1334 4004 1832

Pts selection N+ / inner quadrant N+/ inner quadrant N+ / high risk N0

N0% 40% 44.4% 9.7%

Median Age 57 54 54

Surgery mastectomy 76.1% BCS BCS

chemo % 61 85 91

ER/PR- 7 16 25

HR unknown % 40% 16% unknown

Breast/CW dose Individual discretion 50Gy/25F 50Gy/25F

SC 45Gy/25F both arm study 50Gy/25F Study 45Gy/25F

IMN Study arm 45Gy/25F Study 50Gy/25F Study 45Gy/25F

5MA 20 高危定义：T≥5cm，或T≥2cm，同时<10枚腋窝淋巴结取样，且ER-，G3或淋巴脉管受侵

EORTC 22922/10925

6

Distant metastasis

free survival

OS

ER – tumors:

10-year DFS in the control and RNI

arms ：(71% and 82%, P<0.05);

10-year OS：74% and 81%

P.M.Poortmans et al. N Engl J Med 2015;373:317-27.

MA 20

7

Distant metastasis

free survival

OS

T.J. Whelan N Engl J Med 2015;373:307-16.

• pNmic were ineligible• 10% of patients with left-sided breast cancer did receive IMNI, who

were more frequently had many lymph nodes involved or a medial/central tumor

DBCG-IMN STUDY

Early Stage;

Lymph node

positive

Right-sided

(N=1492)

Fo

llow

-upLeft-sided

(N=1597)

WB/CW+RNI

(With IMN)

N=1437

WB/CW+RNI

(Without IMN)

N=1432

The study was a nationwide, prospective,

population-based cohort study, 2003/1-2007/12

Primary end points was overall survival

Secondary end points were breast cancer mortality and distant recurrence

DOI: 10.1200/JCO.2015.63.6456

8-year OS

(HR=0.82, p=0.005) 75.9% vs. 72.2%

8-year breast cancer mortality

(HR=0.85, p=0.03） 20.9% vs. 23.4%

8-year distant recurrence

(HR=0.89, p=0.07) 27.4% vs. 29.7%

DFS

SUBGROUPS ANALYSIS

• IMNI was more effective in the subgroups of medial/central tumor and/or four or more positive nodes

• the 8-year OS was 72.2% vs. 64.8% in combined subgroup• The adjusted HR for death was 0.76 (P = .001). • The number of patients needed to treat to avoid one death at 8 year

s was 14 (95% CI, 9 to 30).

N1-3+ SUMMARY

MA.20 EORTC22922

HypothesisImprovement of 5% in 5y OS

(80% vs. 85%)

Improvement of 4% in 10y OS

(79% vs. 75%)

Patients 1832 4004

N1-3+ 85% 43.1%

T1-T2 99% 95.8%

BCS 100% 76.1%

Group WBI+RNI vs. WBI WBI/CW+RNI vs. WBI/CW

10-year OS 82.8% vs. 81.8% 82.3% vs. 80.7%

10-year breast cancer

mortality10.3% vs. 12.3% 12.5% vs.14.4%

SUBGROUP BENEFIT FROM RNI

EVOLUTION OF RNI RECOMMENDATION

RS AND LRR

- NSABP B28

1065 ER positive N+ pts

772 N1, 300 N2

461 BCS+WBI, 604 MRM

JNCI J Natl Cancer Inst, 2017, Vol. 109, No. 4

RS showed no significant

prognosis in 1-3 positive

ER+ patients

JNCI J Natl Cancer Inst, 2017, Vol. 109, No. 4

prospective trial is needed to evaluated the

role of RS on radiotherapy

0%

10%

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100%

2012 2013 2014 2015 2016

乳房切除术后T1-2N1的患者接受术后辅助放疗

不详

主诊医生决定

仅伴有不良预后因素

者做所有都做

0%

10%

20%

30%

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100%

2012 2013 2014 2015 2016

保乳术后腋窝淋巴结1-3个转移的患者是否接受区域淋巴结照

射

主诊医生决定

伴有不良预后因素者

否

是

Questionnaire to 15 centers of radiotherapy

For N1，RNI after BCS and PMRT after mastectomy is the choice of

radiation oncologist in majority

TO DEFINE RNI BEYOND ALN

LOW RISK N1?

age

molecular subtype

Number of +ALN

+ALN ratio

multi-gene model

……

HIGH RISK N0?

MA 20：

High risk N0 was defined as T≥5cm; T≥2cm，nodes analyzed＜10 and one of these: ER-, Grade III, LVI+

EORTC 22922/10925:

High risk was defined as centrally or medially located

In house protocol of Institut Curie：

T3, T4，

≤40，multi-foci，LV+，grade III ，HER 2+，TN，PT2 (any of two or above )

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CCTG MA39 “Tailor RT” Phase III TrialWomen > 50 with 1-3 + axillary metastases

ER+ and/or PR+, HER2-Negative,

Luminal A by IHC, ROR , 40, Oncotype-DX RS

18, or Mammaprint low

STRATIFICATION

SNB vs Axillary dissection

Surgery – mastectomy vs BCT

Grade

ENE

RANDOMIZATION

Arm 1

Regional nodal radiation

therapy +

Endocrine therapy

Arm 2

Endocrine therapy

Targeted Accrual: 2100

SLN+ RESEARCH SUMMARY

Trials Tumor size BCS Group Conclusion

Z0011 cT1-2<3 SLN (+)*

95%SLN1-2+100% WBI**/ALND 13.0%

ALND Omitted

when WBI is given

IBCSG 23-

01T≤5cm

Micro SLN (+) ≥ 1

>99%SLN1-2+91% WBI/ ALND 27.8% ALND Omitted

AMAROS cT1-2, cN0SLN(+)

95%SLN1-2+82%

AxRT***/

ALND33%

AxRT can replace

ALND

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*A total of 41% of SLNs were determined to have micrometastases (≤ 2 mm) or isolated tumor cell

**standard tangents or high tangents

***Axillary I/II/III+SC

ALND RECOMMENDATION

Omitting ALND：

•T1-2

•1-2 ALN+

•BCS+WBI

•No preoperative

chemotherapy

Like Z0011, like IBSCG 2301

DOSE TO OAR WHEN AXILLA IS

IRRADIATED

In comparison with high tangents or SC RT,

whole axilla RT is associated with increased

dose to ipsilateral lung

If axilla do necessite RT, more sophisticated

techinique is required.

WANG Shu-Bei et al. Cancer Radiothérapie,

acdepted

IS IT POSSIBLE TO PERSONALIZE ALN RT

BASED ON SLNB NOMOGRAM

SLN1~3+

* MSKCC nomogram; † MDACC nomogram

‡ Katz et al. 2008 JCO

临床病理特征 前哨阳性个数 活检数目

其它淋巴结受累概率 *(%)

其它淋巴结受累概率† (%)

≥4个淋巴结受累概率‡ (%)

射野设计

IDC, 1.0 cm, ER+,

LVI-

1 (微转移) 3 13 8 <1 常规切线

IDC, 1.8 cm, G3,

ER+, LVI-, unifocal

1 (宏转移) 2 27 24 2 高切线

IDC, 2.0 cm, ER-,

LVI+

2 (宏转移) 2 63 55 30 高切线+区域

ILC, 4.0 cm, ER+,

multifocal, LVI-

2 (宏转移) 2 77 64 40 高切线+区域

IDC, 3 cm, ER-,

LVI+, multifocal

3 (宏转移伴ENE)

3 78 95 80 切线+全区域

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2012 2013 2014 2015 2016

保乳术后前哨淋巴结1-2个转移未行腋清的患者主要的放疗策

略为

不详

联合区域淋巴结

高位切线野

常规切线野

0%

10%

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100%

2012 2013 2014 2015 2016

乳房切除术后T1-2前哨淋巴结微转移且未进行腋窝淋

巴结清扫的患者是否接受术后辅助放疗

主诊医生决定

伴有不良预后因素者

基本否

基本是

Questionnaire to 15 centers of radiotherapy

For BCS, SLNB1-2+ without ALND, RNI in addition to whole breast or

high-tangents is the choice of radiation oncologist in majority

More important controversies in pts after mastectomy

PMRT AFTER (NAC)------

CONSENSUS?

No prospective trial evaluating the role of PMRT after NAC

SCORING RESULTS

Scoring 1-3 （no recommendation for PMRT）：

consensus of 80% or above: IIA, IIB, pCR or pN0

Scoring 7-9（recommendation for PMRT）：

consensus of 80% or above: IIB , IIIA, pN+, or IIIC achieving PCR

Controversial population: IIIA/IIIB，achieving pCR or pN0，trends in

favor of PMRT

BENEFIT OF PMRT

ACHIEVING PCR

MD Anderson：

106 pts pCR after NAC

Median F-U 62m

Result：

10-Y LRR 0% in stage I、II pts，with

or without PMRT

In stage III pts, PMRT decreased 10-Y

LRR (7.3% vs. 33.3%,p=0.04)

PMRT ameliorate DFS and OS in

stage III pts

Int J Radiat Oncol Biol Phys, 2007, 68(4): p 1004-1009

KROG 12-05 : NO BENEFIT OF PMRT

IN STAGE II-III YPN0?

151 pts

105 W PMRT, 46 W/O PMRT

Median FU 59 mo

60/151 stage III

Age and pT stage affecting DFS

PMRT might not be necessary for pN0

patients after NAC

Int J Radiation Oncol Biol Phys, Vol. 88, No. 1, pp. 65e72, 2014

BENEFIT OF PMRT IN STAGE IIIB/C PN0

Oncotarget, Vol. 7, No. 17

1560 II-III stage ypN0

903 W PMRT, 657 W/O PMRT

Median FU 56 mo

1004 stage III patients

5-y OS rate: 84.6% for PMRT vs 81.7%

for no PMRT, P = 0.120

PMRT improved OS in patients with

clinical stage IIIB/IIIC disease

NEO-BIOSCORE

A staging system for NAC

patients which incorporated

treatment response and biologic

markers

Biologic markers and multi-gene

were highlighted in AJCC 8

JAMA Oncology. 2016 March 17.

THE ROLE OF NEO-BIOSCORE

FOR RNI AFTER NAC IN YPN0-1

Ruijin hospital

2009- 2014 163 pts

22.1% pCR, 54.6% ypN0，RNI (N=119)

Median FU 59.4 mo

Neo-Bioscore 1-3 (n=92)

5-y DRFS rate: 97% vs. 76.9% for

RNI or not (P=0.002)

5-y RFS rate: 95.5% vs. 76.9% for

RNI or not (P=0.007)

5-y BCSFS rate: 100% vs. 89.2% for

RNI or not (P=0.005)

Lu Cao,et al 2018 ASTRO abstract submitted.

NEO-ADJUVANT RT IN BREAST

RECONSTRUCTION

PMRT is increasingly

recommended for wider

indications

NACT followed by RT and

mastectomy and immediate

free flap reconstruction has

recently been shown to be

safe

NART IN RESTRUCTION RESEARCH

Trials Country Time Stage Treatment Early tocitySatisfaca

tion

5-y

DFS

Pailloch

er et alFrance 1997-2012 111

78% T1-2

40%N0,

54%N1

NART+MR

M+IBR

Seroma 54%

Necrosis 5.4%17/20 93.2%

Monrig

al et alFrance 1990-2008 210 Stage I-III

NART/RT*+

MRM+IBR

Total 21.9%

Necrosis 1% NR 75.6%

Grinsell

et alAustralia 2010-2015 29 NR

NART+MR

M+IBR

Necrosis 3%NR NR

*75 pts were initially treated by BCS and RT but requiring a secondary mastectomy in view of positive margins

HOW TO IRRADIATE RN,

IMN？

34

“CW nodule

invading sternum”

“parasternal

mass”

IMN DELINEATION: IN HOUSE

RECOMMENDATION

superior inferior ventral dorsal medial lateral

IMN Jugulo-

clavicle

junction

or in

continue

with SC

Super

border

of the

4th rib

Ventral

to P

major,

dorsal

of

sternum

Pleural

or IMV 5-

7mm

depth

Pleural or

IMV 7mm

medial,

internal to

cephalic V

Pleural or

IMV 7mm

lateral,

lateral to

cephalic V

Principle of simplification：

1.In continuation with SC

2.In continuation with CW,

depth 5mm of IMV

RADIATION THERAPY AND

IMMUNOTHERAPY

Immunotherapy, a series of agents designed to stimulate

the immune system in order to generate tumor-specific

immune response, is showing promise in treatment of

various cancers

Stone et al., in 1979, found that mice with fibrosarcoma

lacked T-cells required twice as high dose of radiation to

be cured compared to those with T-cells

J Natl Cancer Inst 1979;63:1229e35.

CLINICAL TRIALS OF IMMUNO-

RADIOTHERAPY IN BC

Signals Drugs Trial Phase Disease Statue

TLR

agonists

Imiquimod NCT01421017 I/II MBC Active, not

recruiting

TGF-β Fresolimumab NCT01401062 I/II MBC Active, not

recruiting

LY2157299 NCT02538471 II MBC Active, not

recruiting

OX40 MEDI6469 NCT01862900 I/II MBC(lung or liver) Active, not

recruiting

PD-1/PD-L1 MK-3475 NCT02303366 I oligometastatic BC Completed

Pembrolizumab NCT02730130 II mTNBC Active, not

recruiting

Nivolumab NCT02499367 II mTNBC Recruiting

TAKE HOME MESSAGE

The risk factors for LRR in node positive patients are quite complex

Traditional prognostic factors are basis of RT indications decision

Molecular subtype and 21-gene recurrence score could offer moreinformation

Elective RNI is recommended for SLN+ without ALND pts

Perspective trials needed for individualized RT

Response to NAC complicated RT choice for II-III pts

Staging system (Neo-bioscore) integrated biological information couldprovide guidance

NART followed IBR could be a safe option due to wider indications ofPMRT

Future clinical trials will elucidate the immuno-radiotherapy

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