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Radiotherapy in Breast Cancer: Current Issues

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A brief overview of current issues in radiotherapy of breast cancer, meant mainly for post-grad trainees

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Radiotherapy in Breast Cancer: Current Issues

  1. 1. BREAST CANCER RADIOTHERAPY: CURRENT ISSUES Dr Jyotirup Goswami Department of Radiotherapy Westbank Hospital
  2. 2.  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!
  3. 3. 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
  4. 4. 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
  5. 5. BCS+RT VS MASTECTOMY: RCTS Institute IGR Milan NSABP NCI EORTC Danish B-06 Stage 1 1 1,2 1,2 1,2 1,2,3 Surgery 2cm gross Quad- Lump- Gross excision 1 cm gross Wide excision margin rantectomy ectomy margin Follow-up(y) 15 20 20 18 10 6OS:BCS+RT(%) 73 42 46 59 65 79 M(%) 65 41 47 58 66 82LR: BCS+RT(%) 9 9 14 22 20 3 M(%) 14 2 10 6 12 4
  6. 6. 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
  7. 7. 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).
  8. 8. 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.
  9. 9. BREAST CONSERVATION THERAPY: NODE NEGATIVE DISEASE 5 yr gain 16.1% 15 yr gain 5.1% LR OS EBCTCG Lancet 2005,vol 366, 2093
  10. 10. BREAST CONSERVATION THERAPY: NODE POSITIVE DISEASE LR OS 5 yr gain 30.1% 15 yr gain 7.1% EBCTCG Lancet 2005,vol 366, 2093
  11. 11. 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.
  12. 12. BOOST VS NO BOOSTEORTC 22881-10882 TRIAL Bartelink et al
  13. 13.  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
  14. 14. 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
  15. 15. 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)
  16. 16. BOOST DOSIMETRYDE VS MET VS VMAT Alexander et al
  17. 17. 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.
  18. 18. BREAST CANCER ATLAS For IIB/IIIafter NACT & BCS
  19. 19. REGIONAL NODAL CONTOURING
  20. 20. DURING CT SIMULATION Post-BCS Post-Mastectomy
  21. 21. Breast-superiorBreast-inferior
  22. 22. SCF begins
  23. 23. Axillary level III begins
  24. 24. Axillary level II begins
  25. 25. Axillary level I begins
  26. 26. Axillary level I ends
  27. 27. IMC begins
  28. 28. IMC ends
  29. 29. 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.
  30. 30. 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
  31. 31. 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
  32. 32. APBI: MODALITIES Intra-operative electrons (ELIOT) Intra-operative/ peri-operative HDR interstitial brachytherapy Mammosite Intra-operative orthovoltage X rays (TARGIT)
  33. 33. 20 162 34 10 12 11 5 7
  34. 34. 3D CONFORMAL BRACHYTHERAPY
  35. 35. TARGIT
  36. 36. ELIOT
  37. 37. 3DCRT AND IMRT
  38. 38. MAMMOSITE
  39. 39. COMPARISON OF APBI TECHNIQUES
  40. 40. APBI: CLINICAL RESULTS SO FAR
  41. 41. 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
  42. 42. 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
  43. 43. 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
  44. 44. 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)
  45. 45. EBRT (3DCRT): RESULTS
  46. 46. PROSPECTIVE RCTS OF APBI
  47. 47. 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.
  48. 48. FORWARD PLAN IMRT Courtesy: Budrukkar A
  49. 49. 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)
  50. 50. 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!
  51. 51.  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
  52. 52.  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
  53. 53. 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
  54. 54. 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.
  55. 55. 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.
  56. 56. 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
  57. 57. 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)
  58. 58. 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
  59. 59. 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
  60. 60. THANK YOU

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