Philip Poortmans, MD, PhD 2gbcc.kr/GBCC2017_upload/PFile_01_6_PL5 1_Philip Poortmans.pdf ·...
Transcript of 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
Haute couture tailoring of RT: Introduction
8
Haute couture tailoring of RT: Introduction
9
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
Haute couture tailoring of RT: Introduction
12Courtesy of Marianne Aznar, Rigshospitalet, Copenhagen
RA 5 field IMRT
Free respiration Breath hold
Haute couture tailoring of RT: Introduction
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
Haute couture tailoring of RT: Introduction
16
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
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
Haute couture tailoring of RT: RT & BCT
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
Haute couture tailoring of RT: RT & BCT
20
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
21
Haute couture tailoring of RT: PMRT
EBCTCG. Lancet. 2014;383:2127‐35.
22EBCTCG. Lancet. 2014;383:2127‐35.
Haute couture tailoring of RT: PMRT
23EBCTCG Lancet 2011; 378: 1707–1716 & 2014;383:2127–35.
Haute couture tailoring of RT: PMRT
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.
Haute couture tailoring of RT: PMRT
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.
Haute couture tailoring of RT: PMRT
26
To treat or not
IMN: Balancing Risks and Benefits
27
Haute couture tailoring of RT1. 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
28
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
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
Haute couture tailoring of RT: Surgery or RT?
30van 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
Haute couture tailoring of RT: Surgery or RT?
31van Maaren M, et al. Lancet Oncol. 2016 Aug;17(8):1158‐70.
Haute couture tailoring of RT: Surgery or RT?
BCT = standard for the majority of the pts
BCT = surgery + RT
32
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
Haute couture tailoring of RT: Surgery or RT?
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.
Haute couture tailoring of RT: Surgery or RT?
34Donker M, et al. Lancet Oncol. 2014;15:1303‐10.
Haute couture tailoring of RT: Surgery or RT?
cT1‐2N0 R SNB
Stratification: institutionAdjuvant systemic therapy by choice
ALND
AxRT
AxSN+
AxSN-
EORTC 10981‐22023 “AMAROS”
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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
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Haute couture tailoring of RT: Surgery or RT?ACOSOG Z0011
40
Haute couture tailoring of RT: Surgery or RT?ACOSOG Z0011
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
Haute couture tailoring of RT: Surgery or RT?
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
Haute couture tailoring of RT: Surgery or RT?
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
Haute couture tailoring of RT: Surgery or RT?
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
Haute couture tailoring of RT: Surgery or RT?
Proof of principle:Elective regional treatment less DM improved S
Conclusions – radiation therapy:
45
Haute couture tailoring of RT: Surgery or RT?
• 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
Haute couture tailoring of RT: Surgery or RT?
48
Haute couture tailoring of RT: Surgery or RT?
Protocol Radboud umc, March 2016.
1. Mastectomy for cT1‐4; cN0 (US); no PST
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Haute couture tailoring of RT: Surgery or RT?
Protocol Radboud umc, March 2016.
2. BCT for cT1‐3; cN0 (US); no PST
50
Haute couture tailoring of RT: Surgery or RT?
Protocol Radboud umc, March 2016.
3.1. PST; cN0 (US +/‐ FNA)
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Haute couture tailoring of RT: Surgery or RT?
Protocol Radboud umc, March 2016.
3.2. PST; cN+(1‐3) (US +/‐ FNA); MARI advised
52
Haute couture tailoring of RT1. 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
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
Haute couture tailoring of RT: RT & ST
55
Duplication time
= 3 months
Not detectable at all
Detectable with special techniques
Physically detectable.
Haute couture tailoring of RT: RT & ST
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…
Haute couture tailoring of RT: RT & ST
57
PR
CR
Duplication time
= 3 months
Not detectable at all
Detectable with special techniques
Physically detectable.
Haute couture tailoring of RT: RT & ST
58
Systemic treatment cures breast cancer
Contributes to cure
Haute couture tailoring of RT: RT & ST
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
Haute couture tailoring of RT: RT & ST
61Poortmans P, et al. Breast. 2017;31:295‐302.
Haute couture tailoring of RT: RT & ST
62Poortmans P, et al. Breast. 2017;31:295‐302.
RT after tumourectomy: not always required?
Haute couture tailoring of RT: RT & ST
63Blamey RW, et al. Eur J Cancer. 2013;49:2294‐302.
Haute couture tailoring of RT: RT & ST
64Blamey RW, et al. Eur J Cancer. 2013;49:2294‐302.
Haute couture tailoring of RT: RT & ST
65Blamey 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.
Haute couture tailoring of RT: RT & ST
66Blamey RW, et al. Eur J Cancer. 2013;49:2294‐302.
…, 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
Haute couture tailoring of RT: RT & ST
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
Haute couture tailoring of RT: RT & ST
68Adjuvant!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
Haute couture tailoring of RT: RT & ST
69EBCTCG Lancet 2011; 378: 1707–1716
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%
Haute couture tailoring of RT: RT & ST
70EBCTCG Lancet 2011; 378: 1707–1716
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%
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
Haute couture tailoring of RT: RT & ST
71
Haute couture tailoring of RT: RT & ST
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
Haute couture tailoring of RT: RT & ST
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Haute couture tailoring of RT1. 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
74Poortmans P. Lancet. 2014 Jun 21;383(9935):2104‐6.
Triple -/Her2 type Lum B type Lum A typeNC/PD PR CR
Haute couture tailoring of RT: PST
75Poortmans P. Lancet. 2014 Jun 21;383(9935):2104‐6.
Triple -/Her2 type Lum B type Lum A typeNC/PD PR CR
Lum A; minor R
Haute couture tailoring of RT: PST
76Poortmans P. Lancet. 2014 Jun 21;383(9935):2104‐6.
Triple -/Her2 type Lum B type Lum A typeNC/PD PR CR
---; ypCR
Haute couture tailoring of RT: PST
77Poortmans P. Lancet. 2014 Jun 21;383(9935):2104‐6.
Triple -/Her2 type Lum B type Lum A typeNC/PD PR CR---; NC
Haute couture tailoring of RT: PST
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
Haute couture tailoring of RT: PST
82
Haute couture tailoring of RT: PST
83
Haute couture tailoring of RT: PST
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
Haute couture tailoring of RT: PST Planning‐CT‐scan before and after PST
May 2013: •Major tumour regression on MRI
Treatment: •Continue TAC July 2013•MRM: ypT0ypN0•PMRT + boost on non‐removed nodes
87
Haute couture tailoring of RT: PST Planning‐CT‐scan before and after PST
?
March 2013 September 2013
88
Haute couture tailoring of RT: PST Planning‐CT‐scan before and after PST
March 2013 September 2013
?
89
Haute couture tailoring of RT: PST Planning‐CT‐scan before and after PST
March 2013 September 2013
??!?!
90
Haute couture tailoring of RT: PST
March 2013 September 2013
?OK + !
Planning‐CT‐scan before and after PST
91
Haute couture tailoring of RT: PST Planning‐CT‐scan before and after PST
March 2013 September 2013
OK + ?!?!
92
Haute couture tailoring of RT: PST Planning‐CT‐scan before and after PST
March 2013 September 2013
OK
93
Haute couture tailoring of RT: PST Or even a PET‐CT?
Courtesy of MC Valli and A Fozza
94
Haute couture tailoring of RT1. 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
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
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
98
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
99
Haute couture tailoring of RT: D & C
Early stage, low risk
Long life expectancy: ‐ Surgery + RT
Short life expectancy: ‐ Surgery alone
‐ Endocrine alone
‐ RT alone?
‐ Nothing?
100
Haute couture tailoring of RT: D & C
101Poortmans P, et al. Breast. 2017;31:295‐302.
Haute couture tailoring of RT: D & C
102
Early stage, low risk
Haute couture tailoring of RT: D & C
103
Haute couture tailoring of RT: D & C
104
Early stage, low risk
Haute couture tailoring of RT: D & C
105
Haute couture tailoring of RT: D & C
106
Haute couture tailoring of RT: D & C
Early stage, with risk factors
Long life expectancy: ‐ Surgery with
‐ Systemic T
‐ RT
Short life expectancy: ‐ Surgery with
‐ Systemic T?
‐ RT?
107Poortmans P, et al. Breast. 2017;31:295‐302.
Update 2016: 1.8% LRR at 9 years !!!
We did improve BCT rates!Haute couture tailoring of RT: D & C
108
Haute couture tailoring of RT: D & C
Protocol Radboud umc, March 2016.
109
Haute couture tailoring of RT: D & C
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
Haute couture tailoring of RT: D & C
111
Haute couture tailoring of RT: D & C
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!
115