BREAST CANCER RADIOTHERAPY: CURRENT ISSUES Dr Jyotirup Goswami Department of Radiotherapy Westbank Hospital
The more things change, the more they remain the same: The target, dose, fractionation and delivery modalities are all changing in breast cancer. Yet, some of the key questions of yesterday still remain!
NEW STANDARDS OF CARE IN RADIOTHERAPY OF BREAST CANCER Whole breast RT followed by tumor bed boost APBI Conformal RT IMRT & VMAT Hypofractionated RT Changing indications for post-mastectomy radiotherapy (chest wall & nodal) Prone breast RT
BCS+RT Mastectomy is no longer a standard of care in breast cancer surgery BCS is possible in all EBC and is also practised in LABC Whole breast RT is compulsory in BCT Results of BCS+RT and mastectomy are equivalent Local control rates are also significantly improved by use of boost to tumor bed
The pooled meta-analysis of 15 RCTs shows a threefold reduction in local failure & a small but significantBCS+RT VS BCS improvement in OS with RT after BCS Vinh-Hung et al. JNCI ( 2004);96:115-121
EBCTCG META-ANALYSIS (LANCET 2000) Meta-analysis of 10 Breast cancer mortality and 20 yr results of 40 was significantly RCTs of EBC. reduced N=20 000 However, mortality due 50% node positive to other causes was significantly increased. Local recurrence after BCS was reduced by Absolute increase in approximately 2/3 with 20-yr survival was 2- RT, irrespective of type 4% (except those of RT and stage. women at very low risk of recurrence).
EBCTCG META-ANALYSIS (LANCET 2005) 78 RCTs of EBC. 15-yr breast cancer N= 42 000 mortality was significantly 7300 had BCS reduced, from 35.9% to Local recurrence rate 30.5% at 5 years, after BCS Overall mortality was reduced by post- op RT from 26% to 7%. reduction with RT was 5.3% at 15-yrs. Similar proportional benefit of RT in ALL stages. Absolute benefit varies with the actual risk, according to stage.
BREAST CONSERVATION THERAPY: NODE NEGATIVE DISEASE 5 yr gain 16.1% 15 yr gain 5.1% LR OS EBCTCG Lancet 2005,vol 366, 2093
BREAST CONSERVATION THERAPY: NODE POSITIVE DISEASE LR OS 5 yr gain 30.1% 15 yr gain 7.1% EBCTCG Lancet 2005,vol 366, 2093
EBCTCG META-ANALYSIS (LANCET 2011) 17 RCTs of BCS+RT vs 15-yr breast cancer BCS alone mortality was N= 10 801 significantly (pN0=7287, pN+=1050 reduced, from 25.2% to ) 21.4% ANY recurrence rate at Similar proportional 10 years, after BCS benefit of RT in ALL was reduced by post- stages. Absolute op RT from 35% to benefit varies with the 19.3%. actual risk, according to stage.
BOOST VS NO BOOSTEORTC 22881-10882 TRIAL Bartelink et al
Planning of boost is largely dependant on localisation method and modality used Many centres practise clinical planning, especially if electrons are to be used CT based planning, though preferable, is also problematic Cavity location is not always clear. Also the shape and size of the cavity will change, depending on when the image is taken
SEROMA CONTOURING GUIDELINES STV (Seroma Target Volume)= tumor cavity CTV= STV+1cm (EDITED from skin and chest wall by 5mm) PTV=CTV+1cm STV to EXclude breast tissue stranding, but INclude surgical clips (if present) Wong et al
BOOST MODALITIES En-face electrons HDR brachytherapy 3DCRT/IMRT/VMAT IMPT Modulated electrons (MERT) Electrons are still the commonest and simplest modality. But dosimetrically the most inferior! HDR brachytherapy is a labour intensive, cosmetically demanding, but dosimetrically excellent alternative for deep-seated tumors. (>3cm from skin)
BOOST DOSIMETRYDE VS MET VS VMAT Alexander et al
BREAST CONTOURING GUIDELINES Because more and more centres are doing conformal CT-based planning for breast cancer, contouring guidelines for the intact breast/ chest wall are also increasingly necessary. The RTOG has come up with a Breast Cancer Atlas.
BREAST CANCER ATLAS For IIB/IIIafter NACT & BCS
APBI Twin rationale:(1) Most breast cancer recurrences occur in the index quadrant.(2) Many patients cannot come for prolonged 5-6 week adjuvant radiotherapy for logistic reasons.
APBI: INDICATIONS (ASTRO RECOMMENDATIONS)Suitable outside clinical trial Suitable only in a clinical (ALL of) trial Age>60 years (ANY of) BRCA negative Age 50-59 years T1N0M0 (pT<2cm) BRCA negative EIC negative T1/2,N0,M0 (pT2-3 cm) Unifocal EIC <3cm IDC/ favourable histology Unifocal Margin negative (>2mm) ILC LCIS negative Margin close (<2mm) ER positive ER negative
ASTRO: “UNSUITABLE” FOR APBI ANY OF: T>3cm/T4 or N+ BRCA mutated High grade LVSI extensive EIC+ve (>3cm) Multifocal disease (contraindication to BCS per se) Margin positive Received neoadjuvant chemotherapy
HDR INTERSTITIAL BRACHYTHERAPY: RESULTS Institution Dose Dose Rate Ipsilateral Cosmesis & breast Complications recurrence rateWilliam 32-34 HDR 2.1% (5-yr) >90% achieved goodBeaumont Gy/8-10# to excellent cosmesisHospital,USA 50 Gy LDR 0.9% (5-yr)Ochsner 32-34 HDR 8% 75% achieved good toClinic, USA Gy/8-10# excellent cosmesis 50 Gy LDRLondon 37.2 HDR 16.2% at 5 Median overallRegional Gy/10# yrs* cosmetic score 89%.CancerCentre,Ontario,Canada
HDR INTERSTITIAL BRACHYTHERAPY: RESULTS Institution Dose Dose Rate Ipsilateral Cosmesis & breast Complications recurrence rateNational 30.3-36.4 HDR 6.7% Excellent to goodInstitute of Gy/7# cosmesis in 84.4%.Oncology,HungaryTufts New 34 Gy/10# HDR 6.1% (5-yr 89% had excellentEngland, actuarial) cosmesis at 5 years.USAGuy’s 55 Gy LDR 37%* Cosmesis good toHospital, excellent in 85%.London *= inappropriate selection of patients for APBI
MAMMOSITE: RESULTS Institution Dose Ipsilateral Cosmesis & breast Complications recurrence rateAmerican Society of 34 Gy/10# 1.79% 3-yr Good-excellent cosmesisBreast Surgeons actuarial LRR in >93%.Mammosite BreastBrachytherapyRegistry trial (97institutions)Rush University 34 Gy/10# 5.7% (crude) Good-excellent cosmesisMedical Centre, in 93%.Chicago, USA
IORT: RESULTS Institution Dose Modality Ipsilateral Cosmesis & breast Complications recurrence rateEuropean 21 Gy Electrons 1% Mild/severe fibrosis inInstitute of 3%.Oncology,MilanState 15-20 Gy 120 kV X 29% AcceptableUniversity of raysBuffalo, USAUniversity 20 Gy 50 kV X 0% AcceptableCollege, raysLondon(TARGIT)
IMRT BREAST: WHY? Dosimetric advantages include:(1) better dose homogeneity for whole breast RT(2) better coverage of tumor cavity(3) feasibility of SIB Forward planned IMRT (field-in-field) is preferred as it is simple and effective.
IMPORT TRIALS (PHASE III RCTS FROM UK)IMPORT High: (2008-ongoing) IMPORT Low: (2006-2010) To test dose-escalated IMRT in To test PBI by IMRT in low- high-risk EBC after BCS risk EBC after BCS High risk by v/o (ANY) (ALL) IDC/no ILC/pN0/no N+/grade III/T>2/NACT LVE/pT<3cm/unifocal/grade received/margin<5mm/age 18- I,II or III/margin>2mm 49 yrs/LVE+ 3 arms:3 arms: WBRT (15#/3 weeks) WBRT followed by sequential WBRT +PBI (each 15#/3 boost (56 Gy/23#) weeks) WBRT with SIB (48Gy/15#) PBI (15#/3 weeks) WBRT with SIB (53Gy/15#) Primary endpoint: LocalPrimary endpoint: Breast fibrosis control (ipsilateral)
HYPOFRACTIONATED RT Started as an empirical practice in government-run health care systems of UK and Canada Initially, a purely logistical exercise to reduce treatment duration & create machine space Recently, 2 large trials, START-A and START-B, have validated that clinically as well, hypofractionated RT is safe and effective. In fact, even while delivering a lower BED, the hypofractionated regimens have shown a survival advantage over conventional fractionation!
START-A: (1998-2002) Locoregional relapse N=2236 rates were 3.6%, 3.5% and 5.2%, respectively EBC (pT1-T3a, pN0- N1, M0) BCS=1900 (85%) & Late effects, based on MRM=336 (15%) photographs and patient assessments, were3 arms: significantly lower with 39 50 Gy/25#/5 weeks Gy as compared to 50 Gy 41.6 Gy/13#/5 weeks This trial estimated α/β of 39 Gy/13#/5 weeks breast cancer as 4.6Gy for tumor control and Median FU=5.1 years 3.4Gy for late change in photographic appearance. Lancet Online. March 19,2008
START-B: (1999-2001) Locoregional relapse N=2215 rates were 3.3% and 2.2%, respectively EBC (pT1-T3a, pN0-N1, M0) BCS=2038 (92%) & Absolute differences in MRM=177 (8%) locoregional relapse was - 0.7% (95%CI -1.7% to2 arms: 0.9%), meaning that with 50 Gy/25#/5 weeks 40Gy the relapse rate 40 Gy/15#/3 weeks would be at most 1% worse and at best 1.7% Median FU=6 years BETTER! Lancet Online. March 19,2008
HYPOFRACTIONATION FROM THE RADIOBIOLOGIC VIEWPOINTUK-FAST: (2004-2007) Primary end-point was 2 yr N=915 change in photographic appearance of breast Favourable EBCs after BCS (age>50 yrs, pT<3cm, pN0) 3-yr physician assessed moderate to marked breast adverse effects were 9.5%,3 arms: 11.1% and 17.3% 50Gy/25$/5 weeks respectively. 28.5Gy/5#/5 weeks (once- weekly) Conclusion:At 3 yrs median 30Gy/5#/5 weeks (once- FU, 28.5Gy/5# (@5.7Gy/#) weekly) is comparable to 50Gy/25# for breast adverse effects and significantly milder than Median FU=37.3 months 30Gy/5# (@6Gy/#) Radiotherapy & Oncology. Epub.2011
CHANGING INDICATIONS OF PMRT New indications include: Any AXLN +ve High grade tumors LVE PNI Age <45-50 years pT>2cm Scoring systems are often used.
PN1 VS PN2 FOR CHEST WALL RT Classically, pN2 disease (>=4 positive axillary nodes) was the indication for postmastectomy chest wall RT Subgroup analysis of the DBCG 82 b&c trials (2007) suggested SIMILAR survival benefit of PMRT for 1-3 vs 4+ LN. The St Gallen Consensus (2007) is to treat the SCF even for pN1 (1-3 positive axillary nodes) The SUPREMO trial evaluated the benefit of PMRT in 1-3 axillary lymph node positive patients.
SUPREMO TRIAL (SELECTIVE USE OF POSTOPERATIVE RADIOTHERAPY AFTER MASTECTOMY) Started 2006. Expected to complete end-2012. N=1600 (planned); 1295 Objective: To determine the randomised so far* overall survival of intermediate risk patients pT1-T3 (+/- multifocal ds), treated with post-op RT pN0-N1 (not more than 3 AXLN positive), M0 ,post- MRM Primary endpoint: OS, acute No bilateral breast cancer, & late morbidities margins clear (at least 1mm), no IMC nodes Secondary endpoints: Chemotherapy as required Locoregional recurrence rates, metastasis-free survival, DFS, QoL, cost-2 arms: effectiveness Standard RT to chest wall & SCF Observation *personal communication
IS THERE A ROLE OF AXILLARY NODAL RT? Axillary nodal RT is no longer indicated if complete axillary dissection (>10 LN sampled) has been performed. Axillary nodal RT significantly adds to the lymphoedema morbidity The only possible indications today are: (1) incomplete/ no axillary dissection (2) positive axillary nodes WITH extracapsular extension (ECE)/ perinodal extension (PNE)
IS SCF RT REQUIRED AT ALL? Studies suggest that isolated SCF recurrences are uncommon, for both pN1 and pN3 disease The main risk for pN3 disease, is not SCF recurrence but distant metastasis
PRONE BREAST RT Suitable for pendulous breasts, where breast-only RT is required. Results in significantly better coverage of the breast and significant reduction of dose to the ipsilateral lung. Heart dose remains unchanged. BUT there is significantly more grade 1-2 dermatitis AND setup error. Varga et al