Radiation Oncology Department Polyclinique de Courlancy – REIMS HYPOFRACTIONATED WHOLE BREAST RADIOTHERAPY (RT) AN USEFUL TECHNIQUE FOR THE FUTURE ? Bruno CUTULI MD Radiation Oncology Department Polyclinique de Courlancy – REIMS CORS 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

BCS +/- AD (60%) - Median age : 55 y (< 70 y) ROYAL MARSDEN HOSPITAL STUDY OWEN 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 Weeks RT (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

BCS (85%) or Mastectomy : 15% pN+ : 29% Tamoxifen : 78% - CT : 36% START A TRIAL THE 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

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 LANCET ONCOL 2008, 9 : 331-341

LN irradiation depends of centers START B TRIAL THE 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) 40 Gy / 15 fr – 3 W 2.67 Gy / f 50 Gy / 25 fr – 5 W 2 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 GROUP BREAST 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

Comparison among UK trials : - Local control - Toxicity (Breast change and / or fibrosis)

COMPARISON LOCAL CONTROL RMH / GOC START A START B Courtesy of Y. KIROVA

CANADIAN TRIAL T. 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% CT 11%

RESULTS LOCAL RECURRENCES RATES 5 YEARS 12 YEARS SWBI 3.2% 6.7% AHWBI 2.8% 6.2%

ESSAI CANADIEN Résultats à long terme de la radiothérapie accélérée hypofractionnée Récidive locale 0,1 0,08 6,7 % 0,06 Récidive (%) 6,2 % 0,04 0,02 1 2 3 4 5 6 7 8 9 10 11 12 Années depuis randomisation SWBI 612 597 578 592 550 553 499 485 470 449 410 317 218 AHWBI 622 609 592 569 548 524 500 472 447 430 406 330 214 SABCS 2007 - D’après Whelan T et al., abstract 21 actualisé.

ESSAI CANADIEN Résultats à long terme de la radiothérapie accélérée hypofractionnée Survie globale : 84.5% 0,1 0,08 Survie (%) 0,06 0,04 0,02 1 2 3 4 5 6 7 8 9 10 11 12 À risque Années depuis randomisation SWBI 612 606 594 583 573 559 535 519 505 487 453 355 242 AHWBI 622 617 605 592 576 562 539 517 495 482 455 369 241 SABCS 2007 - D’après Whelan T et al., abstract 21 actualisé.

Florence University experience 539 pts treated between 1997 and 2003 ADJUVANT HYPOFRACTIONATED RADIATION THERAPY FOR BREAST CANCER AFTER CONSERVING SURGERY LIVI L et al Clinical Oncology 2007, 19 : 120-124 Florence University experience 539 pts treated between 1997 and 2003 pT1s (9%), pT1 (79%) or pT2 (12%) Median age : 59 years Median FU : 4.3 years pN+ : 20% CT : 26% TAM : 73% Delivered breast RT dose : 44 Gy/16 f. (2.75/f) 48% : 10 Gy boost

RESULTS Local 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% G3 - 5%

FRENCH RIVIERA EXPERIENCE (2) Long term results of a hypofractionated radiotherapy and hormonal therapy without surgery for breast cancer in elderly patients COURDI 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 Tamoxifen The main reasons for adopting this schedule were patient refusal of surgery, very old age, locally advanced case, and/or comorbid disease RT 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 + RT Median age : 74 years Lumpectomy : 31% Sugery : AD : 94% Quadrantectomy : 69% Standard : 87% Whole Breast RT Hypofractionated (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% NS Hypofractionated 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 2009 Analysis of 367 women older than 70 years treated at CI by BCS + RT for T1T2 BC, between 1995 and 1999 317 (median age : 73 y) : NF-RT (50Gy/25 f, classical) +/- boost 50 (median age : 80 y) : HF-RT (32.5 Gy/6 f), no boost Median 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 séances Parfaite tolérance ou réaction cutanée décalée ? *** Etude prospective de l’Institut Curie BOTTI 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. 3 SEM 5 (FIN RT) 47 15 I 34 59 II 7 47 15 I 34 59 II 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 patientes NB : 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 séances La 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.

Merci de votre attention

COMPARISON TOXICITY % Récidives locales RMH / GOC START A START B Courtesy of Y. KIROVA