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BALKAN MCO 2011 - E. Vrdoljak - Radiotherapy
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  • Figure 1. Outcomes in Patients with Breast Cancer Who Received a Hypofractionated Regimen of Radiation Therapy as Compared with Patients Who Received the Standard Regimen. Panel A shows Kaplan-Meier estimates for local recurrence (P<0.001 for noninferiority), and Panel B shows Kaplan-Meier estimates for overall survival (P=0.79).
  • Figure 2. Hazard Ratios for Ipsilateral Recurrence of Breast Cancer in Subgroups of Patients.
  • Table 1. Late Toxic Effects of Radiation, Assessed According to the RTOG-EORTC Late Radiation Morbidity Scoring Scheme.
  • Table 2. Global Cosmetic Outcome, Assessed According to the EORTC Scale.

BALKAN MCO 2011 - E. Vrdoljak - Radiotherapy BALKAN MCO 2011 - E. Vrdoljak - Radiotherapy Presentation Transcript

  • Radiotherapy for early breast cancer Prof.dr.sc.Eduard Vrdoljak Center of Oncology, Clinical Hospital Split, Croatia
  • Modern breast-saving therapy of breast cancer
    • local cure
    • safety
    • good cosmesis
  • Treatment p lanning 2D versus 3D outline of mid plane mid plane of breast Lung contour Body contour radiograph Conventional Modern
  •  
  • Intensity modulated radiotherapy (IMRT) Heart PTV A B Hurkmans et al . 2002
  • Intraoperative partial breast irradiation
  • Organ motion techniques
    • Breath hold and gating techniques
    • 4-dimensional CT imaging and treatment planning
  • 4D radiotherapy: where is the fourth dimension?
  • 4D CT: sorting process Full respiratory cycle End-inspiration CT Image Sorting Program End-expiration 4 sec
  • Opto-electronic system IR flash IR flash Processing unit Motion analyzer Bunker Control room
  • Breath adapted radiotherapy D eep inspiration breath hold Free breathing Irradiated heart volume 8% Irradiated heart volume 1%
  • 4D radiotherapy ‘ .. is the explicit inclusion of temporal changes in anatomy during imaging, planning and delivery of radiotherapy [Keall ’03] 4D imaging 4D planning 4D delivery 4D CT scans Tumour mobility Normal organ avoidance Respiratory gating
  • Image-guided radiotherapy (IGRT)
    • Full feedback image approach
    • Application during the treatment session
    • Allows high geometric precision and accuracy of radiation delivery
  • T owards optimization of r adiotherapy Treatment and patient tailoring Better imaging Better beam delivery
  • T owards optimization of r adiotherapy Treatment tailoring Better imaging Better beam delivery Integration with targeted therapy Optimal integration with medical therapy
  • DCIS Ductal Carcinoma in Situ
    • MRM is acceptable
      • no node dissection
    • BCT is an acceptable approach if:
      • Lesion is small (< 3 cm)
      • Margins must be negative
        • preferably > 10 mm in all dimensions
      • Adjuvant radiotherapy can be delivered
  • NSABP-17
    • 81 8 pts. with DCIS, negative margins
    • Randomized to RT v s no RT
      • 50 Gy to entire breast, no boost
    • At 12 years, local failure rates
      • 31.7% for no RT
      • 15.7% for RT (p<0.000005)
    • Only marked comedo necrosis was a significant factor predicting for local failure
    • Fisher et al. JCO 1998.
  • EORTC 10853
    • 1010 pts . with DCIS, negative margins
    • Randomized to 50 Gy whole breast or no RT
    • At 10 years, local failure
      • 25 % no RT
      • 15 % with RT (p < 0. 0 00 1 )
      • Age <40 y, grade 2 or 3 -increased risk for local reccurence
      • Bijker et al. JCO 2006.
  • UKCCCR DCIS Working Group
    • 1030 pts with DCIS, negative margins
    • surgery alone
    • surgery + t am oxifen
    • surgery + RT
    • S + RT + t am
    • At 4.4 years, local failure
      • 14% in no RT
      • 6% in RT arm (p<0.0001)
      • Houghton et al. Lancet 2003.
  • Van Nuys Prognostic Index Scores of 3-4 - 98% local control without RT Scores of 5-7 - 32% failed without RT, 16% with RT Scores of 8-9 - 100% failure without RT, 60% with RT
  • Breast Conserving Therapy BCT
    • 70-80% of patients with stage I or II disease are candidates for BCT
    • 6 major randomized trials comparing mastectomy to BCT + RT
      • No difference in DFS
      • No difference in OS
    Jatoi et el. JCO 2005.
  • Distant Failure Jatoi et el. JCO 2005. Trial Pt Time pt. Mast. BCT WHO 1972-79 179 22 yrs 24% 23% Milan I 1973-80 701 20 51% 54% NSABP06 1976-84 1406 20 33% 40% US NCI 1979-89 279 20 34% 39% EORTC 10801 1980-86 903 10 34% 30% Denmark 82TM 1983-89 859 6 32% 34%
  • Local Failure Jatoi et el. JCO 2005. Trial Pt Time pt. Mast. BCT WHO 1972-79 179 22 yrs 14 % 9 % Milan I 1973-80 701 20 2 % 9 % NSABP06 1976-84 1406 20 10 % 14 % US NCI 1979-89 279 20 6 % 22 % EORTC 10801 1980-86 903 10 12 % 2 0% Denmark 82TM 1983-89 859 6 4 % 3%
  • Overall Survival Trial Pt Time pt. Mast. BCT WHO 1972-79 179 22 yrs 41% 42% Milan I 1973-80 701 20 47% 46% NSABP06 1976-84 1406 20 58% 53% US NCI 1979-89 279 20 66% 65% EORTC 10801 1980-86 903 10 79% 82% Denmark 82TM 1983-89 859 6 67% 67%
  • Radiation Technique T1-2 N0
    • Opposed tangential fields
    • Breast only + b oost
    • 50 Gy in 25-28 fractions
    • 42.5 Gy in 16 fractions (Canadian trial )
  • Abbreviated Course of RT
  • Rationale for Abbreviated RT
    • Convenience and c ost
    • More refined radiobiologic estimate of dose equivalence
    • Major improvements in RT delivery with higher energies, 3-D dose calculation and beam modulation -> much greater 3-D dose homogeneity
  • Importance of Dose Homogeneity
    • Tumor control depends on minimal dose while toxicity depends on maximal dose (‘hot spots’)
    • The dose-response curve is very steep so ‘hot spots’ receive not only increased total dose, but greater effective daily dose (‘Double Trouble’)
  • Concerns/Uncertainties
    • Potential effects on late-responding normal tissue (late toxicity)
    • Need long follow up
    • Interaction with systemic therapies, especially adjuvant chemotherapy
    • Patient selection – which patients?
    • Use of a boost
  • Randomized Clinical Trials No significant differences are seen in toxicity or LRR Canadian Start A Start B RMH/GOC Necker Pts 1234 2236 2215 1410 230 Med FU 12 yrs 5.1 yrs 6.0 yrs 9.7 yrs 4 yr Min Arms (Gy x Fx) 2 x 25 2.67 x 16 2 x 25 3 x 13 3.2 x 13 2 x 25 2.67 x 15 2 x 25 3 Gy x 13 3.3 x 13 1.8 x 25 5.75 x 4
  • RANDOMI ZED adjuvant radiotherapy – 16 x 2.67 Gy – no boost adjuvant radi therapy – 25 x 2 Gy – no boost 1234 patients T1 and T2, N0 patients, BCS and ALND Primary endpoint: Local recurrence (LR) Other endpoints: Toxicity, cosmetic results, overall survival (OS) Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer Whelan et al.NEJM 2010.
  • LR and OS LR P<0.001 OS P=0.79
  • Subset Analysis (HRs for LR) Whelan TJ et al. N Engl J Med 2010;362:513-520 ->
  • 10- Yr Toxicity Whelan TJ et al. N Engl J Med 2010;362:513-520 P = NS Standard HypoFx Skin 0 71% 67% 1 22% 24% 2-3 7% 9% Subcut Tissue 0 45% 48% 1 44% 40% 2-3 11% 12%
  • 10-Yr Cosmetic Results Whelan TJ et al. N Engl J Med 2010;362:513-520 P = NS Standard HypoFx Excellent 28% 31% Good 44% 39% Fair 26% 25% Poor 3% 5%
    • “ Ten years after treatment, hypofractionated WBI was not inferior to standard RT in women who had undergone BCS with clear margins and negative axillary nodes”
    • This trial was started prior to the publication of the ‘Boost Trial’
    Conclusion/Caveat
  • EORTC Boost Trial
    • 5569 patients randomized to a 16 Gy
    • boost or no boost after 45 Gy to whole breast
    • The boost reduced 10-year LR by ~
    • 40% and was seen in all subsets
    • The biggest absolute benefit was in
    • younger patients and in g r ade 3 cancers
    Jones HA et al JCO . 2009
  • Patients in the RCT’s Patients older, favorable cancers, chemo/boost not routine Canadian Start A Start B RMH/GOC Necker ER- 27% 21% 12% - - Gr 3 19% 28% 23% - 10% Age < 50 25% 23% 21% 30% - Boost 0% 61% 43% 75% 0% Nodal RT 0% 14% 7% 21% - Chemo 11% 36% 22% 14% 21%
  • ASTRO Guidelines (2010) Smith B et al . IJROBP In Press Age/Stage > 50 yrs, T1,2 N- Surgery BCS Chemotherapy None Fractionation 266 cGy x 16 Heart in Field 0 Boost No Agreement Dose Homogeneity < +/- 7%
  • Clinical Trials in Progress FAST IMPORT High IMPORT Low SHARE RTOG # Pts 915 840 2100 2796 2150 Sites UK UK UK France US Arms (Gy x # Fx) 2 x 25 5.7 x 5 6 x 5 All in 5 weeks 2.4 x 15 integrated boost 2.67 x 15 -> boost 2.67 x 15 2.4 x 15 integrated boost APBI 2.67 x 15 2 x 25 + 2 x 8 2.67 x 15 APBI 4 x 10 2.0 x 25 -> boost 2.67 x 15 integrated boost
  • Summary
    • The available RCT’s, particularly the Canadian Trial with
    • FU =12 yr, have brought new intense focus on its use
    • This approach is clearly indicated in selected patients
    • Undoubtedly, this approach will be increasingly used
  • If getting chemotherapy…
    • Radiation is usually withheld until after the systemic therapy is complete
    • Delay of up to 4-6 months from surgery generally not considered a problem
    • Possible problem with inflammatory cancer or other locally aggressive cancers
    • Hypofractionated schemes may allow for early RT
  • Surgery alone without RT?
    • Patients ≥ 70 years of age
      • stage I, ER+ tumors
      • WBRT + tam vs. no WBRT + tam
    • locoregional failure rate at 10,5 y
    • 1% vs 4%
    • No difference in OS or DFS
    • Hughes et al. JCO 2010
  • Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
    • Meta-analysis results
    • “ Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.”
    • An average of 75% reduction in local failure rates with the addition of RT, in even the lowest risk groups.
    • A survival benefit was seen in the meta-analysis
    • EBCTCG. Lancet 2005.
  • 10 trials of post BCS RT Effect on LR and breast cancer mortality in N- pts BC S BCS + RT BCS BCS + RT
  • 10 trials of post BCS RT Effect on LR and breast cancer mortality in N+ pts BCS BCS + RT BCS + RT BCS
  • The 18-y probability of any DM was significantly higher in No RT vs RT group No RT median time RT median time
  • Main findings I
    • RT reduces the 5-y LR rate both in N + and N - pts
    • The LR rate reduction give a comparable gain in
    • 15-y breast cancer mortality (5%)
    • For every 4 local recurrences avoided, about one
    • breast cancer death will be avoided over the next
    • 15 years
  • Incidence of 2nd cancers and mortality from causes other than breast cancer
  • Breast cancer and overall mortality after BCS/RT BCS + RT BCS BCS + RT BCS
  • Main findings II RT can increase mortality for heart disease and lung cancer and incidence of contr a lateral breast cance r which reduce its net beneficial effect on 15-y breast cancer mortality. Nevertheless, RT produced reductions not only in 15-y breast cancer mortality but also in 15-y overall mortality.
  • All patients need postoperative whole breast ExRT after BCS ?
  • Partial Breast Irradiation (PBI) “radiation of the site of excision and adjacent tissue only”
  • Why PBI ?
    • Less treated volume
    • Less time required
    • Better integration with surgery
    • Better integration with chemotherapy
    • On properly selected patients!
  • Different PBI techniques
    • No dedicated/Dedicated IOERT suite
    • Mobile IOERT accelerator (ELIOT)
    • Low-energy-x-ray system (TARGIT)
    • HDR/LDR-BRT interstitial
    • HDR-BRT baloon catether (Mammosite)
    • External Beam RT/ 3D-CRT/ IMRT
  • Mammosite
  • Am Soc Breast Surgery Mammosite Registry Trial
    • N= 14 49
    • 34 Gy/3,4 Gy fr
    • Catheter placement:
    • 44% at the time of lumpectomy
    • 41% after surgery with US guidance
    • 15% with the scar entry technique
    • Recurrence rate at 3 y = 2,15%
    • Good or excellent cosmesis at 3 y in 91% pts
    • Nelson et al. AJS 200 9.
  • Interstitial Brachytherapy
  • GEC/ESTRO Working Group Study
    • Tumor bed alone (HDR 30.3 in 7 fx or 32 in 8 fx/4 days) vs WBRT (50-50.4 Gy + 10 Gy e-)
    • Stage 0, I or II
    • age 40 years or older
    • unifocal DCIS or invasive carcinoma
    • size < 3 cm
    • clear margins (2 mm, 5 mm for DCIS or lobular)
    • N0 or pN0 (no more than 1 microm e t astases <2mm)
    • Stratification for menopausal status
  • No / Dedicated Linacs IOERT
  • ELIOT
  • 0 20 40 60 80 100 120 0 20 40 60 Depth (mm) Relative dose (%) X-ray source 50kVp (higher RBE) Intrabe a m
  • TARGeted Intraoperative radioTherapy (TARGIT -A ) phase III study
    • IORT vs conventional WBRT , N= 2,232
    • Local recurrence at 4 years 1.2% in targeted intraoperative radiotherapy group vs. 0.95% in WBRT (p=0.4)
    • Toxicity was lower in targeted intraoperative group (0.5% vs 2.1%; p=0.002)
    Vaidya et al. Lancet 2010.
  • ELIOT randomized trial T < 2.5 cm Age > 48 years ELIOT 21 Gy (90% isodose) EXTERNAL RADIOTHERAPY 50 Gy whole breast, 10 Gy boost R Quadrantectomy, SN biopsy/axillary dissection
  • ELIOT delivery
  • ELIOT. Actuarial risk of LF
  • Open questions on PBI
    • Different techniques
    • Different schedule
    • Different patient selection
    • Different treated volume
  • Future directions
  • Radiogenomic
    • Analyze polymorphism of known genes in all individuals
    • Look for phenotypes in specific subgroups
    • Look at the difference in radiation response
  • MOLECULAR MEDICINE: THERAPY
    • Targeted treatment and treatment monitoring
    Molecular therapy Directed at the treatment of a disease in a particular class of patients Molecular radiation therapy Directed at the treatment of biologically characterized targets in a particular patient and condition