GÜNTHER GRUBER Institut für Radio-Onkologie guenther.gruber @ ksa.ch RADIOTHERAPY IN BREAST CANCER (PART 1: CONSERVATION)

GÜNTHER GRUBER

Institut für Radio-Onkologie

guenther.gruber @ ksa.ch

RADIOTHERAPY RADIOTHERAPY IN BREAST CANCERIN BREAST CANCER

(PART 1: CONSERVATION)(PART 1: CONSERVATION)

AIMS OF RTAIMS OF RT

• Breast conservation

• Local control

• Overall survival

• Reduction of side effects

TOPICSTOPICS

• Breast conserving therapy (BCT)

• RT after mastectomy

• Complications

• New trends

BREAST CONSERVATIONBREAST CONSERVATION

NON-INVASIVE CANCERNON-INVASIVE CANCER

RT in LCIS ?RT in LCIS ?



RT in LCIS ?RT in LCIS ?

No solid dataNo solid data

multicentricity (-88%)multicentricity (-88%)contralateral pos. biopsies (-59%)contralateral pos. biopsies (-59%)

10-35% progression to invasive cancer10-35% progression to invasive cancerafter 20 – 25 years follow-upafter 20 – 25 years follow-up



RT in DCIS ?RT in DCIS ?



RT in DCIS ?RT in DCIS ?

Omission of RT ?Omission of RT ?

Omission of RT after Omission of RT after breast conserving surgery for DCISbreast conserving surgery for DCIS

0

10

20

30

40

50

60

70

Los Angeles Detroit

low risk = G1, up to 2cmG2, up to 1cm

high risk => 2cm or G3

SEER data; Katz et al.; J Clin Oncol, 2005

Diagnosis2002


DCISDCIS

VAN NUYS PROGNOSTIC INDEXVAN NUYS PROGNOSTIC INDEX


DCISDCIS

SIZE -15mm 116-40mm 2>40mm 3

G low w/o necrosis 1low with necrosis 2high 3

RR 10+mm 11-9mm 2<1mm 3

New: AGE >60yrs 140 – 60yrs 2<40yrs 3

LOCAL CONTROL: Multivariate analysisLOCAL CONTROL: Multivariate analysisSilverstein, 2002

G Age Size RR


DCISDCIS

Van Nuys series

Prospective study for omission of RTProspective study for omission of RTin ‚good risk‘ (mammo-2.5cm; G1/2; RR 10+mm)in ‚good risk‘ (mammo-2.5cm; G1/2; RR 10+mm)


DCISDCIS

J Wong et al., J Clin Oncol 2006

12 % LR at 5 years !

Stopped early with 158 pts (/200)

Omission of RT in ‚good risk‘ Omission of RT in ‚good risk‘


DCISDCIS

tamoxifenRTOG 9804

tamoxifen + RT

LOCAL CONTROL: Multivariate analysisLOCAL CONTROL: Multivariate analysisSilverstein, 2002

G Age Size RR


DCISDCIS

Van Nuys series

RT

Randomised studies in DCIS with or Randomised studies in DCIS with or without radiotherapywithout radiotherapy

Local control – Efficacy of RTLocal control – Efficacy of RT

Trial n f-up Op Op+RT HR p

NSABP B17 818 5yr 16% 7% 0.43 <0.001

EORTC 10853 1010 10yr 26% 15% 0.53 <0.0001

UKCCCR 1701 5yr 14% 6% 0.38 <0.001

Risk reduction in all subgroups (to various degrees)RT with 50Gy

=> As expected: no difference in overall survival!

Randomised studies in DCIS with or Randomised studies in DCIS with or without radiotherapywithout radiotherapy

Local control – Efficacy of RTLocal control – Efficacy of RT


DCIS – Impact of boost?DCIS – Impact of boost?

median 50 Gy (±1)

median 60 Gy (±1)

Omlin et al. Lancet Oncol, 2006

median: 60Gy (±1)

median: 50Gy (±1)

keine RT



…in young women (-45 years)

Gruber et al., unpublished



…in young women (-45 years)

median: 60Gy (±1)

median: 50Gy (±1)

no RT

Mastectomy

For which pts. with For which pts. with DCIS DCIS radiotherapy canradiotherapy canbe omitted after breast conserving surgery?be omitted after breast conserving surgery?

Evidence-based medicine (3 published studies + 1 as abstract):NO OMISSION OF RT!

Probably yes: clinging or micropapillary growth?; RR ≥ 10mm?(CAVE: young patients! VAN NUYS: >=10mm; <40yrs: n=15!)

Interdisciplinarity is very important !


INVASIVE CANCERINVASIVE CANCER

• BCT vs mastectomy ?


23.3 23.8

41.7 41.2

0

5

10

15

20

25

30

35

40

45

distant meta overall survival

BCT

Mastectomy

Milan I Trial (Mastectomy vs BCT)20 yrs – Results%

Veronesi et al., NEJM 2002 p=0.8 p=1.0


NSABP-06 Trial (Mastectomy vs BCT)20 yrs – Results

5451

54 53

0

10

20

30

40

50

60

distant meta overall survival

BCT

Mastectomy

%

Fisher et al., NEJM 2002 p=0.95 p=0.74


CONCLUSIONCONCLUSION

• BCT + Mastectomy equivalent !



• BCT vs mastectomy ?• Breast conserving surgery: Omission of RT ?


Studies MedianFollow-up

Op LRw/o RT

LRwith RT

NSABP B-06 125 months Lump-ectomy

35% 9%

Scottish Cancer Trial

68 months Lump-ectomy

24% 6%

Uppsala-Örebro Study Group

106 months Segment-ectomy

22% 7%

Ontario Cancer Inst.

91 months Lump-ectomy

35% 11%

Milano III 109 months Quadrant-ectomy

22% 5%

Local relapse: BC surgery +/- RT


10

29.2

17.420.3

13.1

46.5

36.5

45.2

0

510

1520

2530

3540

4550

10yr-LR 10yr-CSS 10yr-LR 10yr-CSS

with RT

w/o RT

EBCTCG 2000 RT metaanalysis, Lancet 12/05

%

p<0.00001 p=0.006 p<0.00001 p<0.01

N0 N+/N?n=6097 n=1214




• BCT + Mastectomy equivalent !• BC surgery: No omission of RT !



• BCT vs mastectomy ?• Breast conserving surgery: Omission of RT ?• Omission of RT in ‚low risk‘ ?


BC surgery +/- RTBC surgery +/- RTSwedish Breast Cancer Group, EJC 2003

median tu-size: 12mm; n=1187;median F-up: 8J

14%

4%


p=0.01

16.5

9.3

2.8

p<0.0001

NSABP B-21, n=1009; JCO 2002

BC surgery +/- RT, pT1a/pT1b pN0


Local relapse rates, pT1a/pT1b pN0

Age 70+ ?

Therapy,-ies n LR

TAM 43 3 (7%)RT 59 5 (8%)TAM+RT 57 0

RT vs. TAM => HR 1.06 (0.25-4.46) !NSABP B-21, n=1009 JCO, 2002


CALGB, RTOG, ECOG (Hughes et al. NEJM, 9/2004)

n=636 (75+ years: 55%)median F-up: 5J

… in T1, N0, R0, ER+ (in 97%), >70yrs

LOCAL RELAPSE

with tamoxifen 4%with tamoxifen and RT 1%

p<0.001


T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.)

5yrs LR

-2cm, R0, HR+ n=611

Tam 3.2%Tam + WB-RT 0.4% (p<0.001)

-1cm, R0, HR+ n=263

Tam 2.6%Tam + WB-RT 0% (p=0.02)

Files et al., NEJM 2004



5yrs LR 8yrs LR

-2cm, R0, HR+ n=611

Tam 3.2% 15.2% Tam + WB-RT 0.4% (p<0.001) 3.6%

-1cm, R0, HR+ n=263

Tam 2.6%Tam + WB-RT 0% (p=0.02)

+ 3J

x 5 !




5yrs LR 8yrs LR

-2cm, R0, HR+ n=611 (B21)

Tam 3.2% 15.2% (16.5%) Tam + WB-RT 0.4% (p<0.001) 3.6% ( 2.8%)

-1cm, R0, HR+ n=263

Tam 2.6%Tam + WB-RT 0% (p=0.02)

+ 3J

x 5 !



ABCSG 8 (8A) (Pötter et al. ASTRO, OEGRO, ECCO 13, 11/2005)

n=826 (60+ years: about two thirds)median F-up: 42 mo

postmenop., T <3cm, N0, ER+ and/or PR+

LOCAL RELAPSE 5yrs

with Tamoxifen/AI 4.5%with Tamoxifen/AI and RT 0.6%

p=0.001


„„low risk“ – studieslow risk“ – studiessummary

Follow up still too short !No subgroup of pts. which does not profit from RT!

IMPORTANT: Trade-offs !

If overall survival > 5yrs: RT !



• BCT + Mastectomy equivalent !• BC surgery: No omission of RT !• No omission of RT in ‚low risk‘ !



• BCT vs mastectomy ?• Breast conserving surgery: Omission of RT ?• Omission of RT in ‚low risk‘ ?• PBI for ‚low risk‘ ?



RATIONALE for PBI

small RT volume offers the possibility for highersingle doses=> Shorter treatment time (4-5 days vs 5 weeks)

Socio-economic aspects

small RT volume has likely less long-termcomplications

RT of whole breast necessary ?


‚ Never change a winning team ! ‘(whole breast irradiation)

Less experience !

Target volume ?

Residual tumor cells ?

Patient selection ?


PROBLEMS for PBI

Local relapse out of ‚tu bearing quadrant‘

TRIALTRIAL f-up f-up OPOP OP+RT OP+RT

NSABP-B06 125 2.7% 3.8%MAILAND 39 1.5% 0%UPPSALA 64 3.5%ONTARIO 43 3.5% 1.0%

Modified after Baglan et al., 2001

RANDOMISED STUDIESRANDOMISED STUDIES


Intraoperative Radiotherapy

in Phase III


in Phase III

Interstitial Brachytherapy (iBT)

Most data in the literature are based on iBT !

in Phase III



Brachytherapy-Ballon (Mammosite ®)

In USA very frequent !

in Phase III


Brachytherapy-Ballon (Mammosite ®)


Registry Trial; n=1449; Median f-up: 14 mo

2yrs local failure: 1.2% (isolated LF 0.8%)

2yrs axillary failure: 1.0% (isolated AF 0.6%)

Good/excellent cosmesis6mo 12mo 18mo 24mo 36mo95.1% 93.7% 91.3% 93.5% 90.4%

Vicini F et al. ASCO; 2006

3D (IMRT; protons) percutaneous RT

Few data !

in Phase III


PBI only

William Beaumont HospitalWilliam Beaumont Hospitaln=199 (92% pT1), f-up: 65mon=199 (92% pT1), f-up: 65moHDR: 32 Gy / 8fx / 4dHDR: 32 Gy / 8fx / 4dLDR: 50 Gy, 0.52Gy/h, 96hLDR: 50 Gy, 0.52Gy/h, 96h

actuarial LR (5J)actuarial LR (5J)WB-RT: 1% PBI: 1%

PBI as good as WB-RT !

Vicini et al., 2003


Manchester Trial (Phase III); 1982-87; n = 708;

Breast + LN (4MV;40Gy/15fx)Randomisation

PBI (10MeV; 40-42.5Gy/8fx)• no axillary diss.• no systemic therapy• no microscopic resection margin determination• in 42% no Tumor size determination

11%LOCAL REL.

20%

PBI only


„„low risk“ – PBI?low risk“ – PBI?Summary

(So far) no standard !Phase III studies ongoing !Anyway, only for ‚low risk‘ !Expertise ?



• BCT + Mastectomy equivalent !• BC surgery: No omission of RT !• No omission of RT in ‚low risk‘ !• The target is the whole breast !



• BCT vs mastectomy ?• Breast conserving surgery: Omission of RT ?• Omission of RT in ‚low risk‘ ?• PBI for ‚low risk‘ ?• Altered fractionation?


altered fractionationaltered fractionation

Whelan et al., JNCI 94, 2002

Stage I/IIn=1234

median f-up : 69 months

R

42.5Gy/2.65Gy22 daysn=622

50Gy/2Gy35 daysn=612


Whelan et al., JNCI 94, 2002

LRFS DFS

100%

95%




Owen et al., Lancet Oncol, 2006

T1-3 N0-1n=1410

median f-up : 9.7 years

R

42.9Gy/3.3Gy5 wksn=466

50Gy/2Gy5 wksn=470


39Gy/3Gy5 wksn=474




HR LR 5yrs 10yrs




50Gy 1 7.9% 12.1%

42.9Gy 0.86 7.1% 9.6%

39Gy 1.33 9.1% 14.8%

=> alpha/beta is 4 (95%CI 1-7.8); 41.6Gy/3.2Gy = 50Gy/2Gy!


• BCT + Mastectomy equivalent !• BC surgery: No omission of RT !• No omission of RT in ‚low risk‘ !• The target is the whole breast !• There are equivalent schedules !



• BCT vs mastectomy ?• Breast conserving surgery: Omission of RT ?• Omission of RT in ‚low risk‘ ?• PBI for ‚low risk‘ ?• Altered fractionation?• Increase of dose (boost) ?


Local recurrences after BCS + RT BOOST versus NO BOOST

no boost boost H.R.

• Lyon 5 y 4.5 % 3.6 % (10 Gy) 0.80 p = 0.044

n = 1024

• French M.C. 5 y 6.8 % 3.6 % (16Gy) 0.53 p = 0.13

n = 664

• EORTC 10801 5 y 6.8 % 3.4 % (15Gy) 0.59 p = 0.0001

n = 5569


BREAST-RT +/- BOOSTBREAST-RT +/- BOOST

p=0.002 p=0.02

p=0.07 p=0.11

- 40J (n=449) 41-50J (n=1334)

51-60J (n=1803) > 60J (n=1732)

Bartelink et al., NEJM 2001


Breast pain – randomised study

Whelan et al., Cancer 2000

no RT

RT

*

*

p<0.01


Skin reactions – randomised study

RT

no RT


*

*

p<0.01


Breast cosmesis – randomised study


no RT

RT


Global score by boost treatment

No boost Boost0

20

40

60

80

100%

Excellent/Good

Fair/Poor

71%

29%

86%

14%




• BCT + Mastectomy equivalent !• BC surgery: No omission of RT !• No omission of RT in ‚low risk‘ !• The target is the whole breast !• There are equivalent schedules !• Boost efficient (! <50yrs !)


RT – BREAST CANCERRT – BREAST CANCER‚‚TIMING‘TIMING‘


‚‚TIMING‘ RT – HTTIMING‘ RT – HT

In vitro

Radioresistence , Ø, by Tamoxifen

In vivo

Only 2 studies(Labrie et al.; Cancer Res. 1999; Int J Cancer 2003)


‚‚TIMING‘ RT – HTTIMING‘ RT – HT

ZR-75-1 human breast cancer cells (s.c. into nude mice)=> average tumor-area 20mm2; Strata: tumor size

RT 15x2GyEM-800 300ug/d (SERM)

Day 1 21 156

ARM A

ARM B

CR: 62% CR: 62% (arm A) vs. 22% vs. 22% (arm B)

RRT 15x2Gy

EM-800 300ug/d (SERM)

24 mice

24 mice


RT – Tamoxifen: simultaneous vs sequentialRT – Tamoxifen: simultaneous vs sequential

Journal of Clinical Oncology, Vol 23, No 1, 2005* 3 (small) retrospective studies

LRFSOS

z.B. Ahn et al, 2005


Lokalrezidiv

Bentzen, S. M. et al. JCO; 23:6266-6267 2005

RT – Tamoxifen: simultaneous vs sequentialRT – Tamoxifen: simultaneous vs sequential


RT – 6xCMF: ‚RT first‘ vs ,CMF first‘RT – 6xCMF: ‚RT first‘ vs ,CMF first‘

Bellon, J. R. et al. JCO; 23:1934-1940; 2005

DFS


Breast conservation; n=244

No significant difference!



DMFSDFS








OSDMFSDFS


‚‚ChT => RT‘ vs ,simChT/RT‘ChT => RT‘ vs ,simChT/RT‘

Toledano et al.; Int J Radiat Oncol Biol Phys; 2006


ChT= mitoxantrone, 5-FU, cyclophosphamide; 6 cyclesRT= 50Gy/2Gy; +/- boost

ARCOSEIN III trial (n=214 for late toxicity)

! No difference in acute toxicity !(skin, esophagus, infections, neutropenia)! No statistical difference in grade 2 or higherbreast edema, lymphedema, pain !! simChT/RT: Significant more breast atrophy,subcutaneous fibrosis, teleangiectasia, skin pigmentation !

RT – Herceptin ®RT – Herceptin ®


RT – Herceptin ®RT – Herceptin ®

Halyard MY et al. ASCO; 2006


N9831: AC->T->H vs AC->TH->HRT (after BCS or Mx4+LN sim to H allowed)

1460 available for adverse events analysesmedian f-up: 1.5yrs

Skin reaction (p=0.78); pneumonitis (p=0.78), dyspnea (p=0.87)Cough (p=0.54); dysphagea (p=0.26); neutropenia (p=0.16)

Concurrent H-RT is not associated with acute RT adverse events Further follow up is needed for late adverse events

IndividualHT: simultaneous possibleChT: In most centers: ChT -> RT

simultaneous RChT possible but more side effects!=> Not recommended


How to combine RT with systemic therapies ?

Herc: simultaneous possible

TECHNIQUE / RT APPLICATIONTECHNIQUE / RT APPLICATION



Planning-CT and 3D-Planning




Hurkmans et al., 2001Hurkmans et al., 2001

42 mm

HEART


„Open“ homogeneous beam (OB)

Intensity modulatedbeam (IMB)


IMRT


IMRT

IMRT

IMRT

IMRT


R

Standard 2D 3D IMRT

5yrs – Differences in breast appearence (Photos)

60% 48% p=0.06

(QoL no difference)

n=306

Yarnold et al., ECCO 13; 2005


IMRT

6MV + 12e Protons

IMRTIMRTLomax et al. IJROBP 2003


‚Organ‘motion, n=20

‚motion‘ within 1 fraction: 1.3 +/- 0.4 mm‘motion’ between 2 fractions: 2.6 +/- 1.3 mm

Kron et al., ESTRO 2004


SCHLUSSFOLGERUNGSCHLUSSFOLGERUNG


RT – BREAST CANCERRT – BREAST CANCERRE-IRRADIATIONRE-IRRADIATION

Documents

GÜNTHER GRUBER Institut für Radio-Onkologie guenther.gruber @ ksa.ch RADIOTHERAPY IN BREAST CANCER (PART 1: CONSERVATION)