1. Department of Clinical Radiotherapy, Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK R4 한재준 1

2. Introduction Early breast cancer prescribed radiotherapy after tumor excision or mastectomy. Radiotherapy reduces the risk of local relapse by about 70% and reduces breast cancer mortality. Effective dose is adjusted to balance the risk of local cancer recurrence against the risk of harmful effects on healthy tissues. The most frequently used schedule worldwide is 50Gy, delivered in 25 fractions. 2

3. Introduction Normal and malignant tissues vary in their responses to radiotherapy fraction size, termed fractionation sensitivity. Fractionation sensitivity= Sensitivity/fraction size= a/b Sensitivity measured by – the degree of tissue damage for normal tissues – tumor recurrence rates for malignant tumors 3

4. Introduction Healthy tissues of the breast and ribcage are – sensitive to fraction size with a/b values 5Gy or less – so small changes in the fraction size can produce relatively large changes in the effects of radiotherapy on these tissues. This change is typical of so-called late-reacting normal tissues that take months or years to develop atrophy or fibrosis after radiotherapy. 4

5. Introduction Squamous carcinomas of the lung and the head and neck area – high a/b values 10 Gy or more – indicating low sensitivity to fraction size In head and neck cancer radiotherapy delivered in small fractions (2Gy or less) to a high total dose spares late-responding normal tissues relative to tumor. 5

6. Introduction Breast cancer – has previously been thought to be insensitive to fraction size and best treated with fractions of 2.0 Gy or less. However, some trials have tested the hypothesis – breast cancer is as sensitive to fraction size as the normal tissues of the breast and underlying rib cage. If confirmed, these findings could indicate that small fraction sizes of 2Gy or lower offer no therapeutic advantage a more effective strategy would be to deliver fewer, larger fractions to a lower total dose. 6

7. Patients Women with operable invasive breast cancer (pT1-3a pN0-1 M0) requiring radiotherapy after surgery (breast conserving surgery or mastectomy, with clear margins >=1mm) aged over 18 years did not have an immediate surgical reconstruction available for follow up From 13 centers Between 1998 and 2002 7

8. Procedure Principal end points – Local-regional tumor relapse – Late normal tissue effects – Quality of life Changes in breast appearance – Photographs were taken at baseline and then at 2 and 5 years to assess change in size, shrinkage, and shape, and scored on a 3 point graded scale. 8

9. Results 9

10. Demographic and clinical characteristics 10

11. Results 11

12. Results 12

13. Results 13 Kaplan-Meier plot of mild/marked change in breast appearance shows that the treatment differences were evident at 2 years, and persisted to 5 years

14. Results 14 Forest plot of late normal tissue effects assessed from photographs showing Generally favor of the 39Gy group compared with 50Gy Similar rates of effects after 41.6Gy compared with 50Gy

15. Results 15 The incidence was low at this stage during follow up and balanced between the schedules.

16. Discussion The results of START Trial A are consistent with the hypothesis that breast cancer is as sensitive to fraction size as the normal tissues. 41.6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of normal tissue effects and also interms of local tumor control. The fractionation sensitivity of breast cancer: a/b ratio of 4.8 Gy a/b ratio for normal tissue: 3.4 Gy from the photographic assessments 16

17. Discussion Breast cancer seems to respond differently to human squamous carcinomas of the bronchus and head and neck region, and to experimental animal tumours characterised by α/β values of 10 Gy or more. It contributes to accumulating evidence that cancers vary in their sensitivity to fraction size. The molecular mechanisms governing fractionation sensitivity are not yet understood, but the cellular correlates include recovery from sub-lethal and potentially lethal damage. 17

18. Conclusion The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41·6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects. A lower total dose in a smaller number of fractions could offer similar rates of tumor control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions. 18