HYPOFRACTIONATED WHOLE BREAST

RADIOTHERAPY (RT)AN USEFUL TECHNIQUE FOR THE FUTURE ?

Bruno CUTULI MDRadiation Oncology Department

Polyclinique de Courlancy – REIMSCORS MEETING

JUAN LES PINS 27-06-2009

Altough whole breast RT after conservative surgery is a well established standard, it is still underused, especially in elderly people (20-25% in U.S)

On the other hand, in several countries, RT resources are quite limited and / or very restricted to large cities inducing long delays for RT treatment

Thus, since 1986, several « alternative » RT schemes have been used in order to « simplify » treatment modalities and offer a wider access to patients

In 1995, a preliminary study was published by the Institut Curie team (MAHER M. et al IJRBOP 1995, 31 : 783-789)70 women of 81-year median age were treated between 1988 and 1994 by hypofractionated RT and Tamoxifen (5x6.5 Gy to whole breast + 2 x 6.5 Gy to tumor bed once a week)There were 38 T1T2 and 32 T3T4 (with 28 N1-N2)

RESULTS AT 36 MONTHS

Local control : 86%

Disease specific survival : 88%

…This study demonstrates that very high rates of loco-regional control are achievable using Tamoxifen and high dose per fraction once- weekly RT

ROYAL MARSDEN HOSPITAL STUDYOWEN JR LANCET 2006, 7 : 467-471

1410 PATIENTS INCLUDED FROM 1986 TO 1998

BCS +/- AD (60%) - Median age : 55 y (< 70 y)T1T2 : 94% - pN+ : 37% (out of 60%)Tamoxifen : 64% - CT : 14%

5 WeeksRT (Randomization)

50 Gy / 25 fr. 49.9 Gy / 13 fr. 39 Gy / 13 fr.

RMH / GOC STUDY LOCAL CONTROL – F.U : 9.7 y – 1410

PTS

Courtesy of Y. KIROVA

RMH / GOC STUDY LATE TOXICITY

Courtesy of Y. KIROVA

START A TRIALTHE START TRIALIST’S GROUP

2236 PTS INCLUDED IN 17 UK CENTERS FROM 1998 TO 2002

BCS (85%) or Mastectomy : 15%pN+ : 29% Tamoxifen : 78% - CT : 36%LN irradiation depends of centers

RT (Randomization)

50 Gy / 25 fr.2 Gy / f

41.6 Gy / 13 fr.3.2 Gy / f

39 Gy / 13 fr.3 Gy / f

NB : 61% 10 Gy Boost (e-) Lancet Oncol 2008, 331-341

LANCET ONCOL 2008, 9 : 331-341

START A TRIAL

LANCET ONCOL 2008, 9 : 331-341

START A TRIAL

LANCET ONCOL 2008, 9 : 331-341

START A TRIAL

LANCET ONCOL 2008, 9 : 331-341

INCIDENCE OF ISCHAEMIC HEART DISEASE SYMPTOMATIC RIB FRACTURE AND SYMPTOMATIC LUNG FIBROSIS ACCORDING TO FRACTIONATION

SCHEDULE

START B TRIALTHE START TRIALIST’S GROUP Lancet Oncol 2008, 371 : 1098-1107

2215 PTS INCLUDED IN 23 CENTERS FROM 1999 TO 2001

BCS : 92% or Mastectomy : 8%pN+ : 23% Tamoxifen : 86% - CT : 22%LN irradiation depends of centers

RT (Randomization)

50 Gy / 25 fr – 5 W2 Gy / f

40 Gy / 15 fr – 3 W2.67 Gy / f

NB : 43% 10 Gy Boost

START B 2225 PTS FU : 6 YEARS. LOCAL

RECURRENCES :

3.3% 50 Gy

2% 40 Gy

START B 923 PTS SUB GROUPBREAST CONSERVING SURGERY AND RT :

ESTHETIC RESULTS

INCIDENCE OF ISCHAEMIC HEART DISEASE SYMPTOMATIC RIB FRACTURE AND SYMPTOMATIC LUNG

FIBROSIS ACCORDING TO FRACTIONATION SCHEDULE

LANCET ONCOL 2008, 371 : 1104

CANADIAN TRIALT. WHELAN et al JNCI 2002, 94 : 1143-5

SABCS 2007 : Abs 6

1234 women treated from 1993 to 1996

50 Gy/25f / 35 days

(Long arm = SWBI)pT1T2N0 : BCS + RT

42.5 Gy/16f / 22 days(Short arm = AHWBI)

BASELINE CHARACTERISTICS

SWBI(612)

AHWBI(622)

AGE > 50Y 76% 75%

T1 67% 69%

TAMOXIFEN 41% 41%

CT 11% 11%

RESULTSLOCAL RECURRENCES RATES

5 YEARS 12 YEARS

SWBI 3.2% 6.7%

AHWBI 2.8% 6.2%

ESSAI CANADIEN

Récidive localeRécidive locale

SABCS 2007 - D’après Whelan T et al., abstract 21 actualisé.

0,1

0,08

0,06

0,04

0,02

0

6,2 %

Années depuis randomisation0 2 4 6 8 10 12

6,7 %

Ré

cid

ive

(%

)

1 3 5 7 9 11

612

622

578

592

550

548

499

500

470

447

410

406

218

214

597

609

592

569

553

524

485

472

449

430

317

330

SWBI

AHWBI

Résultats à long terme de la radiothérapie accélérée hypofractionnée

ESSAI CANADIEN

SABCS 2007 - D’après Whelan T et al., abstract 21 actualisé.

Survie globale : 84.5%Survie globale : 84.5%0,1

0,08

0,06

0,04

0,02

0

Années depuis randomisation0 2 4 6 8 10 12

Su

rvie

(%

)

1 3 5 7 9 11

612

622

594

605

573

576

535

539

505

495

453

455

242

241

606

617

583

592

559

562

519

517

487

482

355

369

SWBI

AHWBI

À risque

Résultats à long terme de la radiothérapie accélérée hypofractionnée

ADJUVANT HYPOFRACTIONATED RADIATION THERAPY FOR BREAST CANCER AFTER

CONSERVING SURGERYLIVI L et al Clinical Oncology 2007, 19 : 120-124

Florence University experience539 pts treated between 1997 and 2003 pT1s (9%), pT1 (79%) or pT2 (12%) Median age : 59 yearsMedian FU : 4.3 yearspN+ : 20% CT : 26% TAM : 73%Delivered breast RT dose : 44 Gy/16 f. (2.75/f)48% : 10 Gy boost

RESULTSLocal relapse : 10 / 539 1.8%

negative : 1.7%Margins

(p=0.05)positive : 7%

40 y : 11%Age (p=0.04)

> 40 y : 1.5%

Yes : 0.5%Tamoxifen (p=0.0001)

No : 5.3%

Grade 2 : 21%Fibrosis

Grade 3 : 2.5%(No correlation with CT and / or breast volume)

LIVI Clin Oncol 2007, 19 : 120- 4

FRENCH RIVIERA EXPERIENCE (1) Long term results of adjuvant

hypofractionated radiotherapy for breast cancer in elderly patients

ORTHOLAN C et al IJROBP 2005, 61 : 154-162

150 pts (median age : 78 years) treated between 1987 and 1999 by surgery (BCS : 72%, mastectomy : 28%) and hypofractionated RT (5x6.5 Gy once a week)Boost : 33%Tam : 76%Median FU : 65 months

RESULTS

Local recurrence : 2.3%

DFS : 5y 80% 10y 71%

OS : 5y 72% 10y 46%

DSS : 5y 89% 10y 77%

ORTHOLAN C et al IJROBP 2005, 61 : 154-162

SIDE EFFECTS

ACUTE(Erythema)

LATE(Fibrosis)

G1 19% 30%

G2 9% 19%

G3 - 5%

FRENCH RIVIERA EXPERIENCE (2) Long term results of a hypofractionated

radiotherapy and hormonal therapy without surgery for breast cancer

in elderly patientsCOURDI A. et al Radiother Oncol 2006, 79 : 156-161

115 pts (median age : 83 years) with 124 BC treated between 1987 AND 1999 by HFRT and TamoxifenThe main reasons for adopting this schedule were patient refusal of surgery, very old age, locally advanced case, and/or comorbid diseaseRT was delivered as once-a-week, 6.5 Gy for total dose of 32.5 Gy in 5 fractions, followed with 1-3 fractions of 6.5 Gy to the tumor site

RESULTS

Median FU : 41 months

Local failure : 19 cases : 15%

5-year local progression-free rate : 78%

Breast cancer deaths : 26%

COURDI RADIOTH ONCO 2006, 79 : 156-161

COURDI RADIOTH ONCO 2006, 79 : 156-161

FRANCO-ITALIAN EXPERIENCE

910 women (with 927 treated breast) older than 70 years treated from 1983 to 2000 in three French Centers (TOULOUSE, STRASBOURG, NANCY) and two Italian Centers (BRESCIA, PERUGIA) for a pT1T2 BC by BCS + RTMedian age : 74 years

Lumpectomy : 31%Sugery : AD : 94%Quadrantectomy : 69%

Standard : 87%Whole Breast RTHypofractionated (Toulouse) : 13%

pN+ : 30.6%

Tamoxifen : 56%

CT : 50%

RESULTS

Median FU : 65 months

Local recurrences : 28 / 927 3%

Nodal recurrences : 9 / 927 0.7%

Metastases : 26 / 910 3%

Contralateral BC :51 / 910 5.6%

LOCAL RECURRENCE RATES

Classical RT (50 Gy/25 f +/- 10 Gy Boost) : 2.7%

NSHypofractionated RT (32.5 Gy/6 f) : 3.7%

METASTATIC RISK FACTOR

CUTULI B. ONCOL HEMATOL 2009, 71 : 79-88

CURIE INSTITUTE EXPERIENCE

Breast-conserving treatment in the elderly : long-term results of

adjuvant hypofractionated and normofractionated radiotherapy

KIROVA Y IJROBP 2009Analysis of 367 women older than 70 years treated at CI by BCS + RT for T1T2 BC, between 1995 and 1999317 (median age : 73 y) : NF-RT (50Gy/25 f, classical) +/- boost50 (median age : 80 y) : HF-RT (32.5 Gy/6 f), no boostMedian FU : 93 months

LOCAL RECURRENCE RATES

5 Y 7 Y

NF – RT (317)

5% 7%

HF – RT (50) 6% 9%

KIROVA INT J RADIAT ONCOL BIOL PHYS. 2009

KIROVA INT J RADIAT ONCOL BIOL PHYS. 2009

DISEASE SPECIFIC SURVIVAL RATES

5 Y 7 Y

NF – RT (317)

96% 93%

HF – RT (50) 95% 87%

KIROVA INT J RADIAT ONCOL BIOL PHYS. 2009

KIROVA INT J RADIAT ONCOL BIOL PHYS. 2009

KIROVA INT J RADIAT ONCOL BIOL PHYS. 2009

La Radiothérapie mammaire hypofractionnée en 13

séancesParfaite tolérance ou réaction

cutanée décalée ?

***Etude prospective de l’Institut

CurieBOTTI M. et al

Cancer Radiothérapie, in press

METHODE :Recueil prospectif entre 02/2006 et 03/2007 de toutes les patientes recevant à l’IC une RT mammaire adjuvante de 42,9 Gy en 13 fractions (3.3 Gy/f – 3 sem.) et 5 semaines

POPULATION :- 81 patientes de 40 à 83 ans (age médian : 70 a)- T0 : 53 - T2 : 5- T1 : 21 - T3T4 : 2- Pas de CT ou HT concomitante- 17 TTS en DD et 64 en D2

REACTIONS CUTANEES

GRADE SEM. 3SEM 5

(FIN RT)

0 47 15

I 34 59

II 0 7

Les auteurs ont noté dans ¼ des cas des réactions cutanées de G II 15 jours après la fin de la RT et préconisent une consultation de surveillance pour ces patientesNB : Aucune réaction de grade III-IV n’a été notée

CONCLUSION

La radiothérapie hypofractionnée, en particulier à doses modérées (2.7 – 3.3 Gy/f) semble une alternative de traitement intéressante tout spécialement pour les patientes âgées, permettant soit une réduction de la durée globale du traitement, soit un espacement des séancesLa tolérance immédiate est satisfaisante et les résultats carcinologiques sont équivalents à ceux du traitement classique.La toxicité à long terme semble également acceptable, surtout avec l’optimisation des techniques. Des études complémentaires sont nécessaires.

COMPARISON TOXICITY

0

5

10

15

20

25

30

35

40

45

50

50 42.9 39 50 41.6 39 50 40

% R

écid

ives

locale

s

RMH / GOC START A START B

Courtesy of Y. KIROVA