philip poortmans, md, phd 2gbcc.kr/gbcc2017_upload/pfile_01_6_pl5 1_philip poortmans.pdf ·...

2Philip Poortmans, MD, PhD

Past‐President

President‐Elect

3

Haute couture tailoring of radiation

therapy in breast cancer

4

I have no conflicts of interest

5

Haute couture tailoring of RT

1. Introduction• General

• The role of radiation therapy in BCT

• The role of PMRT

2. Interaction with other treatments

• Surgery or radiation therapy?

• Competition with systemic therapy?

• The case of primary systemic therapy

3. Discussion & Conclusions

6

Haute couture tailoring of RT: Introduction

7


8


10

Contemporary radiation therapyHaute couture tailoring of RT: Introduction

11Offersen BV, et al. Radiother Oncol 2015;114:3‐10 & 2016;118:205‐8.

• Breast

• Boost

• PBI

• Thoracic wall

• LN supraclavicular

• LN axilla level III

• LN axilla level II

• LN axilla Rotter

• LN axilla level I

• LN internal mammaryHeart


12Courtesy of Marianne Aznar, Rigshospitalet, Copenhagen

RA 5 field IMRT

Free respiration Breath hold


13Poortmans P, et al. Breast. 2017;31:295‐302.

Update 2016: 1.8% LRR at 9 years !!!

The role of radiation therapy in BCTHaute couture tailoring of RT: Introduction

14Iyer VR, et al Science 1999;283:83‐7; Chang HY, et al PLoS Biology 2004;2:E7.

In vitro Wound Model – 516 genes

Prognostic Significance in

• Breast

• Lung

• Gastric cancer

Wound Response SignatureHaute couture tailoring of RT: Introduction

15Nuyten DS et al, Breast Cancer Res. 2006;8(5):R62.

Predict of Local Recurrence in Early Breast Cancer

0

0.10.2

0.30.4

0.5

0.60.7

0.80.9

1

0 2 4 6 8 10 12

Activated

Quiescent0

0.1

0.2

0.3

0.4

0.50.6

0.7

0.8

0.9

1

0 2 4 6 8 10 12

Activated

Quiescent P=0.0005P=0.00014

Training Validation

High Risk

Low Risk

High Risk

Low Risk


16










17

Haute couture tailoring of RT: RT & BCT

EBCTCG Lancet 2011; 378: 1707–1716

18EBCTCG Lancet 2011; 378: 1707–1716

0 Gy

50 Gy

0 Gy

50 Gy

Effect of RT after BCS on recurrence and breast cancer mortality in pN+ women.

‐21.2% ‐ 8.5%2.5:1


19

Effect of RT after BCS on recurrence and breast cancer mortality in pN0 women.

0 Gy

50 Gy

0 Gy

50 Gy

‐15.4% ‐ 3.3%5:1

EBCTCG Lancet 2011; 378: 1707–1716


20










21

Haute couture tailoring of RT: PMRT

EBCTCG. Lancet. 2014;383:2127‐35.

22EBCTCG. Lancet. 2014;383:2127‐35.


23EBCTCG Lancet 2011; 378: 1707–1716 & 2014;383:2127–35.


Interpretation: RT reduced both recurrence and breast cancer mortality in women with positive lymph nodes.

24EBCTCG Lancet 2011; 378: 1707–1716 & 2014;383:2127–35.


Interpretation: RT reduced both recurrence and breast cancer mortality in women with positive lymph nodes.

Similar effects:

• Irrespective of the number of involved lymph nodes

• Whether systemic therapy was given or not

• More benefit after partial or no AD

• Less benefit if only regional RT

25

Are the internal mammary lymph nodes a target?

Harris JR, Hellman S.

Put the "hockey stick" on ice.

IJROBP 1988;15:497‐9.


26

To treat or not

IMN: Balancing Risks and Benefits

27

Haute couture tailoring of RT1. Introduction

• General



2. Interaction with other treatments• Surgery or radiation therapy?




28

1. Introduction

• General







Haute couture tailoring of RT: Surgery or RT?

29van Maaren M, et al. Lancet Oncol. 2016 Aug;17(8):1158‐70.

Dutch population based cancer registry

2000‐2004 cohort: 37,207 patients

- 58.4% BCT

- 41.6% MRM



Dutch population based cancer registry

2000‐2004 cohort: 37,207 patients

- 58.4% BCT

- 41.6% MRM




BCT = standard for the majority of the pts

BCT = surgery + RT

32

1. Introduction

• General








33

5,4% (95% CI = 2,7 – 8,0%)

TAM: 5,6 – 10,9%

CHT (<50J): 7,0 – 11,0%

CHT (>50J): 2,0 – 3,0%

PRE‐SLN ERA:

Impact of ALN on overall survival

Orr RK, Ann Surg Oncol. 1999;6:109‐16.


34Donker M, et al. Lancet Oncol. 2014;15:1303‐10.


cT1‐2N0 R SNB

Stratification: institutionAdjuvant systemic therapy by choice

ALND

AxRT

AxSN+

AxSN-

EORTC 10981‐22023 “AMAROS”

35

Haute couture tailoring of RT: Surgery or RT?EORTC 10981‐22023 “AMAROS”

RT‐fields: inappropriate (too large)!!!

ARM

36Donker M, et al. Lancet Oncol. 2014;15:1303‐10.

Haute couture tailoring of RT: Surgery or RT?EORTC 10981‐22023 “AMAROS”

0

5

10

15

20

25

30

35

40

1 3 5

ALND

AxRT

28.0%

40.0%

29.8%

21.7%

16.7%13.6%

Years after randomization

%

P < 0.0001 P < 0.0001P < 0.0001

Lymph

edem

aClinical observatio

n an

d/or trea

tmen

t

N0

no axillary treatm

ent: ???

N0

no axillary treatm

ent: ???

N0

no axillary treatm

ent: ???

37Giuliano AE et al. JAMA 2011;305:569‐75.

Haute couture tailoring of RT: Surgery or RT?ACOSOG Z0011

T1/T2 cN0 Breast Cancer

BCT + SLNB

pN1

pN0

RANDOM

ALD No ALD

No ALD

All patients received tangential field

irradiation without a third field

39


40


Kuehn T, Poortmans P. Breast Care 2011;6:154‐157.

• 165 investigators from 177 departments

median accrual = 1 patient/year/investigator

QA?????

• Fields for breast irradiation not clearly defined

41


ALND: 39.4% 21.2%

SLNB: 43.7% 16.9%

ACOSOG Z0011: QART: 228 replies (= the best 29%?)

Jagsi R, et al. J Clin Oncol 2014;32:3600‐6.

42


Jagsi R, et al. J Clin Oncol 2014;32:3600‐6.

ALND: 0.56cm = part L1‐2‐3‐Rotter

SLNB: 0.69cm = part L1‐2‐3‐Rotter

ACOSOG Z0011: QART: 228 replies (= the best 29%?)

43AMAROS + Z0011


Conclusions – surgery:

Both ALND and AxRT provide excellent and comparable locoregional control in AxSN+ patients

Significantly less lymphedema after AxRT

AxRT can be considered standard

44


Proof of principle:Elective regional treatment less DM improved S

Conclusions – radiation therapy:

45


• Axillary surgery can be omitted

• Regional RT improves outcome

• No surgery ≠ no radiation therapy!

Median FU

+/‐ 6 years +/‐ 10 years

Conclusions – surgery & radiation therapy:

46

Haute couture tailoring of RT: Surgery or RT?Should we treat the axilla – and who does it?

47

consensus agreements


48


Protocol Radboud umc, March 2016.

1. Mastectomy for cT1‐4; cN0 (US); no PST

49



2. BCT for cT1‐3; cN0 (US); no PST

50



3.1. PST; cN0 (US +/‐ FNA)

51



3.2. PST; cN+(1‐3) (US +/‐ FNA); MARI advised

52


• General







53

What is the size of a cancer cell

= 0,01 mm3

Haute couture tailoring of RT: RT & ST

54

21

84

3216

.64

.

1.000.000.000 = 1 cc = 1 grams.

3-6 months3-6 months3-6 months3-6 months3-6 months3-6 months 8-12 years


55

Duplication time

= 3 months

Not detectable at all

Detectable with special techniques

Physically detectable.


56

So what is a “complete pathological remission"?

• Resection specimen = 100 grams 100.000.000.000 cells

• Do you know a pathologist who can perform a complete evaluation?

• It will rather be around 1 to 5% of the material…


57

PR

CR

Duplication time

= 3 months

Not detectable at all

Detectable with special techniques

Physically detectable.


58

Systemic treatment cures breast cancer

Contributes to cure


59Poortmans P. Lancet. 2014 Jun 21;383(9935):2104‐6.

1/4

1/2-3

1/1.5

1/

1/4

Interaction systemic and locoregional treatmentsHaute couture tailoring of RT: RT & ST

60

RT & survival:

Competition/interaction with surgery and systemic treatment

↓ risk for death < M+ ↑ importance of LC

earlier stage BC

improved systemic therapy

X



RT after tumourectomy: not always required?


63Blamey RW, et al. Eur J Cancer. 2013;49:2294‐302.



Even in these patients with tumours of excellent

prognosis, LR after conservative surgery without

adjuvant therapy was still very high. This was

reduced to a similar extent by either radiotherapy

or tamoxifen but to a greater extent by the

receipt of both treatments.



…, LR after conservative surgery without

adjuvant therapy was still very high…

Personal note:

Virtually none of those pts would get adjuvant

systemic treatment according to the Dutch guidelines


67Adjuvant!Online

Stage Benefit HT Benefit HT(all 65y;N0;ER+;Her-) DFS (%) OS (%)

T1a-bG1-3 4.9-9.5 0.3-1.4T1cG1 5.7-8.2 0.9T1cG2 7.8-11.1 2.0T1cG3 9.6-13.9 3.3

T2<3cmG1 8.1-11.6 2.4T2<3cmG2 10.8-15.7 4.3T2<3cmG3 12.7-18.7 5.9


68Adjuvant!Online


T1a-bG1-3 4.9-9.5 0.3-1.4T1cG1 5.7-8.2 0.9T1cG2 7.8-11.1 2.0T1cG3 9.6-13.9 3.3

T2<3cmG1 8.1-11.6 2.4T2<3cmG2 10.8-15.7 4.3T2<3cmG3 12.7-18.7 5.9


69EBCTCG Lancet 2011; 378: 1707–1716


0 Gy

50 Gy

0 Gy

50 Gy

‐15.4% ‐ 3.3%


70EBCTCG Lancet 2011; 378: 1707–1716


0 Gy

50 Gy

0 Gy

50 Gy

‐15.4% ‐ 3.3%


T1a-bG1-3 4.9-9.5 0.3-1.4T1cG1 5.7-8.2 0.9T1cG2 7.8-11.1 2.0T1cG3 9.6-13.9 3.3

T2<3cmG1 8.1-11.6 2.4T2<3cmG2 10.8-15.7 4.3T2<3cmG3 12.7-18.7 5.9


71


72Jagsi R Ca Cancer J 2014;64:135‐162.

“Studies seeking to identify a subgroup of patients who

could undergo breast conserving surgery without radiotherapy, based upon

clinicopathologic characteristics alone have

largely proved unsuccessful”

The eternal quest


73


• General








Triple -/Her2 type Lum B type Lum A typeNC/PD PR CR

Haute couture tailoring of RT: PST



Lum A; minor R




---; ypCR



Triple -/Her2 type Lum B type Lum A typeNC/PD PR CR---; NC


78Sachelarie, et al. The Oncologist 2006;11:574‐589

Haute couture tailoring of RT: PST Primary or adjuvant systemic therapy?

79Huang EH, et al. J Clin Oncol 2004;22:4691-9

Haute couture tailoring of RT: PST 6 studies (713 pts) PST + surgery ± RT

80McGuire SE. IJROBP 2007;68:1004‐9.

Haute couture tailoring of RT: PST 226 pts PST pCR + surgery ± RT

81


82


83


Other tools to individualise:

• Response to PST (= predictor of RLR risk)

• Pre‐PST stage incl histology; VI; molecular profile; …

• Age

84

Haute couture tailoring of RT: PST A technical radiation oncology note

85

Haute couture tailoring of RT: PST Planning‐CT‐scan before and after PST

March 2013: patient age 49•Tumour central in left breast: •Biopsy (histology): IDA G3; triple –•FNA axillary LN: +•FNA supraclavicular LN: +•Conclusion after staging: cT3N3M0

Treatment: PST•Referred for evaluation by RO•TAC x 6

86


May 2013: •Major tumour regression on MRI

Treatment: •Continue TAC July 2013•MRM: ypT0ypN0•PMRT + boost on non‐removed nodes

87


?

March 2013 September 2013

88



?

89



??!?!

90



?OK + !

Planning‐CT‐scan before and after PST

91



OK + ?!?!

92



OK

93

Haute couture tailoring of RT: PST Or even a PET‐CT?

Courtesy of MC Valli and A Fozza

94


• General








95

Haute couture tailoring of RT: D & CEvidence tells us to reserve surgery for

macroscopic resectabledisease and radiation therapy for all others!

Regional treatment improves outcome!

Use treatment protocols, register data and

continue finetuning!

Current & future trials are superfluous; results will be outdated before they

are known!

96

Haute couture tailoring of RT: D & C

Biological + technological optimisation personalised/individualised/stratified approaches.

Management of women with early stage & low‐risk breast cancer: PROMs & PREMs.

Management of women with advanced stage & high‐risk breast cancer: individualised intensification.

Precision radiation medicine

97






98






99


Early stage, low risk

Long life expectancy: ‐ Surgery + RT

Short life expectancy: ‐ Surgery alone

‐ Endocrine alone

‐ RT alone?

‐ Nothing?

100


102



103


104



105


106


Early stage, with risk factors

Long life expectancy: ‐ Surgery with

‐ Systemic T

‐ RT

Short life expectancy: ‐ Surgery with

‐ Systemic T?

‐ RT?


Update 2016: 1.8% LRR at 9 years !!!

We did improve BCT rates!Haute couture tailoring of RT: D & C

108



109


Advanced stage, with risk factors

Long life expectancy: ‐ Surgery with

‐ Systemic T

‐ RT

Short life expectancy: ‐ Surgery with

‐ Systemic T

‐ RT

110Source: Globocan, 2008. Rates shown are age‐standardised rate per 100,000 using the standard world population.

Incidence

Mortality

1/2.5 1/6


111


Salvador Dalí: Don Quijote de la Mancha

112

Haute couture tailoring of RT: Conclusions

Predictive molecular and genetic testing of normal tissue and tumour responsiveness.

The role of the immune system and host response.

Test general hypotheses relating to radiation genomics and normal tissue responses.

Large databases incl radionomics

Nanoparticles as radiosensitisers.

Sequential/serial biopsies.

Overall treatment time.

Still a lot of work to be done!

113

Haute couture tailoring of RT: Acknowledgements

‐ Harry Bartelink‐ Laurence Collette‐ Sarah Darby‐ Birgitte Offersen‐ Roberto Orecchia‐ Oliver Ott‐ John Yarnold‐ Icro Meattini‐ Meritxell Arenas‐ Lorenzo Livi‐ And many others!

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