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

    • 1. Radiotherapy for early breast cancer Prof.dr.sc.Eduard Vrdoljak Center of Oncology, Clinical Hospital Split, Croatia
    • 2. Modern breast-saving therapy of breast cancer <ul><li>local cure </li></ul><ul><li>safety </li></ul><ul><li>good cosmesis </li></ul>
    • 3. Treatment p lanning 2D versus 3D outline of mid plane mid plane of breast Lung contour Body contour radiograph Conventional Modern
    • 4.  
    • 5. Intensity modulated radiotherapy (IMRT) Heart PTV A B Hurkmans et al . 2002
    • 6. Intraoperative partial breast irradiation
    • 7. Organ motion techniques <ul><li>Breath hold and gating techniques </li></ul><ul><li>4-dimensional CT imaging and treatment planning </li></ul>
    • 8. 4D radiotherapy: where is the fourth dimension?
    • 9. 4D CT: sorting process Full respiratory cycle End-inspiration CT Image Sorting Program End-expiration 4 sec
    • 10. Opto-electronic system IR flash IR flash Processing unit Motion analyzer Bunker Control room
    • 11. Breath adapted radiotherapy D eep inspiration breath hold Free breathing Irradiated heart volume 8% Irradiated heart volume 1%
    • 12. 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
    • 13. Image-guided radiotherapy (IGRT) <ul><li>Full feedback image approach </li></ul><ul><li>Application during the treatment session </li></ul><ul><li>Allows high geometric precision and accuracy of radiation delivery </li></ul>
    • 14. T owards optimization of r adiotherapy Treatment and patient tailoring Better imaging Better beam delivery
    • 15. T owards optimization of r adiotherapy Treatment tailoring Better imaging Better beam delivery Integration with targeted therapy Optimal integration with medical therapy
    • 16. DCIS Ductal Carcinoma in Situ <ul><li>MRM is acceptable </li></ul><ul><ul><li>no node dissection </li></ul></ul><ul><li>BCT is an acceptable approach if: </li></ul><ul><ul><li>Lesion is small (< 3 cm) </li></ul></ul><ul><ul><li>Margins must be negative </li></ul></ul><ul><ul><ul><li>preferably > 10 mm in all dimensions </li></ul></ul></ul><ul><ul><li>Adjuvant radiotherapy can be delivered </li></ul></ul>
    • 17. NSABP-17 <ul><li>81 8 pts. with DCIS, negative margins </li></ul><ul><li>Randomized to RT v s no RT </li></ul><ul><ul><li>50 Gy to entire breast, no boost </li></ul></ul><ul><li>At 12 years, local failure rates </li></ul><ul><ul><li>31.7% for no RT </li></ul></ul><ul><ul><li>15.7% for RT (p<0.000005) </li></ul></ul><ul><li>Only marked comedo necrosis was a significant factor predicting for local failure </li></ul><ul><li>Fisher et al. JCO 1998. </li></ul>
    • 18. EORTC 10853 <ul><li>1010 pts . with DCIS, negative margins </li></ul><ul><li>Randomized to 50 Gy whole breast or no RT </li></ul><ul><li>At 10 years, local failure </li></ul><ul><ul><li>25 % no RT </li></ul></ul><ul><ul><li>15 % with RT (p < 0. 0 00 1 ) </li></ul></ul><ul><ul><li>Age <40 y, grade 2 or 3 -increased risk for local reccurence </li></ul></ul><ul><ul><li>Bijker et al. JCO 2006. </li></ul></ul>
    • 19. UKCCCR DCIS Working Group <ul><li>1030 pts with DCIS, negative margins </li></ul><ul><li>surgery alone </li></ul><ul><li>surgery + t am oxifen </li></ul><ul><li>surgery + RT </li></ul><ul><li>S + RT + t am </li></ul><ul><li>At 4.4 years, local failure </li></ul><ul><ul><li>14% in no RT </li></ul></ul><ul><ul><li>6% in RT arm (p<0.0001) </li></ul></ul><ul><ul><li>Houghton et al. Lancet 2003. </li></ul></ul>
    • 20. 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
    • 21. Breast Conserving Therapy BCT <ul><li>70-80% of patients with stage I or II disease are candidates for BCT </li></ul><ul><li>6 major randomized trials comparing mastectomy to BCT + RT </li></ul><ul><ul><li>No difference in DFS </li></ul></ul><ul><ul><li>No difference in OS </li></ul></ul>Jatoi et el. JCO 2005.
    • 22. 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%
    • 23. 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%
    • 24. 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%
    • 25. Radiation Technique T1-2 N0 <ul><li>Opposed tangential fields </li></ul><ul><li>Breast only + b oost </li></ul><ul><li>50 Gy in 25-28 fractions </li></ul><ul><li>42.5 Gy in 16 fractions (Canadian trial ) </li></ul>
    • 26. Abbreviated Course of RT
    • 27. Rationale for Abbreviated RT <ul><li>Convenience and c ost </li></ul><ul><li>More refined radiobiologic estimate of dose equivalence </li></ul><ul><li>Major improvements in RT delivery with higher energies, 3-D dose calculation and beam modulation -> much greater 3-D dose homogeneity </li></ul>
    • 28. Importance of Dose Homogeneity <ul><li>Tumor control depends on minimal dose while toxicity depends on maximal dose (‘hot spots’) </li></ul><ul><li>The dose-response curve is very steep so ‘hot spots’ receive not only increased total dose, but greater effective daily dose (‘Double Trouble’) </li></ul>
    • 29. Concerns/Uncertainties <ul><li>Potential effects on late-responding normal tissue (late toxicity) </li></ul><ul><li>Need long follow up </li></ul><ul><li>Interaction with systemic therapies, especially adjuvant chemotherapy </li></ul><ul><li>Patient selection – which patients? </li></ul><ul><li>Use of a boost </li></ul>
    • 30. 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
    • 31. 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.
    • 32. LR and OS LR P<0.001 OS P=0.79
    • 33. Subset Analysis (HRs for LR) Whelan TJ et al. N Engl J Med 2010;362:513-520 ->
    • 34. 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%
    • 35. 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%
    • 36. <ul><li>“ 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” </li></ul><ul><li>This trial was started prior to the publication of the ‘Boost Trial’ </li></ul>Conclusion/Caveat
    • 37. EORTC Boost Trial <ul><li>5569 patients randomized to a 16 Gy </li></ul><ul><li>boost or no boost after 45 Gy to whole breast </li></ul><ul><li>The boost reduced 10-year LR by ~ </li></ul><ul><li>40% and was seen in all subsets </li></ul><ul><li>The biggest absolute benefit was in </li></ul><ul><li>younger patients and in g r ade 3 cancers </li></ul>Jones HA et al JCO . 2009
    • 38. 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%
    • 39. 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%
    • 40. 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
    • 41. Summary <ul><li>The available RCT’s, particularly the Canadian Trial with </li></ul><ul><li>FU =12 yr, have brought new intense focus on its use </li></ul><ul><li>This approach is clearly indicated in selected patients </li></ul><ul><li>Undoubtedly, this approach will be increasingly used </li></ul>
    • 42. If getting chemotherapy… <ul><li>Radiation is usually withheld until after the systemic therapy is complete </li></ul><ul><li>Delay of up to 4-6 months from surgery generally not considered a problem </li></ul><ul><li>Possible problem with inflammatory cancer or other locally aggressive cancers </li></ul><ul><li>Hypofractionated schemes may allow for early RT </li></ul>
    • 43. Surgery alone without RT? <ul><li>Patients ≥ 70 years of age </li></ul><ul><ul><li>stage I, ER+ tumors </li></ul></ul><ul><ul><li>WBRT + tam vs. no WBRT + tam </li></ul></ul><ul><li>locoregional failure rate at 10,5 y </li></ul><ul><li>1% vs 4% </li></ul><ul><li>No difference in OS or DFS </li></ul><ul><li>Hughes et al. JCO 2010 </li></ul>
    • 44. Early Breast Cancer Trialists' Collaborative Group (EBCTCG) <ul><li>Meta-analysis results </li></ul><ul><li>“ 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.” </li></ul><ul><li>An average of 75% reduction in local failure rates with the addition of RT, in even the lowest risk groups. </li></ul><ul><li>A survival benefit was seen in the meta-analysis </li></ul><ul><li>EBCTCG. Lancet 2005. </li></ul>
    • 45. 10 trials of post BCS RT Effect on LR and breast cancer mortality in N- pts BC S BCS + RT BCS BCS + RT
    • 46. 10 trials of post BCS RT Effect on LR and breast cancer mortality in N+ pts BCS BCS + RT BCS + RT BCS
    • 47. The 18-y probability of any DM was significantly higher in No RT vs RT group No RT median time RT median time
    • 48. Main findings I <ul><li>RT reduces the 5-y LR rate both in N + and N - pts </li></ul><ul><li>The LR rate reduction give a comparable gain in </li></ul><ul><li>15-y breast cancer mortality (5%) </li></ul><ul><li>For every 4 local recurrences avoided, about one </li></ul><ul><li>breast cancer death will be avoided over the next </li></ul><ul><li>15 years </li></ul>
    • 49. Incidence of 2nd cancers and mortality from causes other than breast cancer
    • 50. Breast cancer and overall mortality after BCS/RT BCS + RT BCS BCS + RT BCS
    • 51. 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.
    • 52. All patients need postoperative whole breast ExRT after BCS ?
    • 53. Partial Breast Irradiation (PBI) “radiation of the site of excision and adjacent tissue only”
    • 54. Why PBI ? <ul><li>Less treated volume </li></ul><ul><li>Less time required </li></ul><ul><li>Better integration with surgery </li></ul><ul><li>Better integration with chemotherapy </li></ul><ul><li>On properly selected patients! </li></ul>
    • 55. Different PBI techniques <ul><li>No dedicated/Dedicated IOERT suite </li></ul><ul><li>Mobile IOERT accelerator (ELIOT) </li></ul><ul><li>Low-energy-x-ray system (TARGIT) </li></ul><ul><li>HDR/LDR-BRT interstitial </li></ul><ul><li>HDR-BRT baloon catether (Mammosite) </li></ul><ul><li>External Beam RT/ 3D-CRT/ IMRT </li></ul>
    • 56. Mammosite
    • 57. Am Soc Breast Surgery Mammosite Registry Trial <ul><li>N= 14 49 </li></ul><ul><li>34 Gy/3,4 Gy fr </li></ul><ul><li>Catheter placement: </li></ul><ul><li>44% at the time of lumpectomy </li></ul><ul><li>41% after surgery with US guidance </li></ul><ul><li>15% with the scar entry technique </li></ul><ul><li>Recurrence rate at 3 y = 2,15% </li></ul><ul><li>Good or excellent cosmesis at 3 y in 91% pts </li></ul><ul><li>Nelson et al. AJS 200 9. </li></ul>
    • 58. Interstitial Brachytherapy
    • 59. GEC/ESTRO Working Group Study <ul><li>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-) </li></ul><ul><li>Stage 0, I or II </li></ul><ul><li>age 40 years or older </li></ul><ul><li>unifocal DCIS or invasive carcinoma </li></ul><ul><li>size < 3 cm </li></ul><ul><li>clear margins (2 mm, 5 mm for DCIS or lobular) </li></ul><ul><li>N0 or pN0 (no more than 1 microm e t astases <2mm) </li></ul><ul><li>Stratification for menopausal status </li></ul>
    • 60. No / Dedicated Linacs IOERT
    • 61. ELIOT
    • 62. 0 20 40 60 80 100 120 0 20 40 60 Depth (mm) Relative dose (%) X-ray source 50kVp (higher RBE) Intrabe a m
    • 63. TARGeted Intraoperative radioTherapy (TARGIT -A ) phase III study <ul><li>IORT vs conventional WBRT , N= 2,232 </li></ul><ul><li>Local recurrence at 4 years 1.2% in targeted intraoperative radiotherapy group vs. 0.95% in WBRT (p=0.4) </li></ul><ul><li>Toxicity was lower in targeted intraoperative group (0.5% vs 2.1%; p=0.002) </li></ul>Vaidya et al. Lancet 2010.
    • 64. 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
    • 65. ELIOT delivery
    • 66. ELIOT. Actuarial risk of LF
    • 67. Open questions on PBI <ul><li>Different techniques </li></ul><ul><li>Different schedule </li></ul><ul><li>Different patient selection </li></ul><ul><li>Different treated volume </li></ul>
    • 68. Future directions
    • 69. Radiogenomic <ul><li>Analyze polymorphism of known genes in all individuals </li></ul><ul><li>Look for phenotypes in specific subgroups </li></ul><ul><li>Look at the difference in radiation response </li></ul>
    • 70. MOLECULAR MEDICINE: THERAPY <ul><li>Targeted treatment and treatment monitoring </li></ul>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

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