1. Rib fracture after 177 patients with Hiroshi Onishi, Hiroshi Onishi, Rihito Tominaga, Marino, Takafumi Komiyama, Kengo University of Yamanashi,

2. stereotactic body stage I non-small Tsuyota Koshiishi, Shinichi Aoki. Kuriyama, Eiichi Sawada, Atsushi Yamanashi, Japan

3. radiotherapy in cell lung cancer Masayuki Araya, Ryo Saito, Kan Nambu, Naoki Sano, Tsutomu Araki

4. Background Despite the increasing popularity of SBRT, experience with extremely hypofractionated, high-dose radiotherapy regimens and their posttreatment radiologic findings and clinical toxicity remains limited. Multiple Phase I and II SBRT studies of the treatment of Stage I-II NSCLC have reported chest wall (CW) pain and/or rib fracture as a part of the toxicity profile. But an exact frequency of rib fracture after SBRT and risk factors for it was unknown.

5. Purpose The aim of the study was to assess the relationship between the background of factors in patients or the treatment and the development of rib fracture*. * Definition of the rib fracture in the study : A CT findings of linear line indicating fracture on rib on high dose-irradiated area

6. Total cases Age Stage Tumor diameter Distance to chest wall 177 (male 132, female 45) 55-92 (median 78) years T1N0M0 118, T2N0M0 59 8-55 (median 25) mm 0-53 (median 6) mm Patients characteristics Irradiated from 2001.11 to 2009.4 Dose and prescription Total dose / fractionations/ days 40Gy / 10 fr / 4-7 days 48 Gy / 4 fr / 4-7 days 60 Gy / 10 fr / 5-8 days 70 Gy / 10 fr / 5-8 days BED(  =3Gy) 93.3 Gy 240 Gy 180 Gy 233.3 Gy Prescription D95(PTV) Isocenter D95(PTV)

7. SBRT planning 1)Instruct patient to reproduce patients’ self-judged breath-holds according to a respiratory indicator (ABCHES). 2) Measurement of reproducibility of the patient’s self-inspired breath-hold by 3 times of CT scanning 3)Three dimensional (3D) treatment planning was performed. Planning target volume (PTV) was defined as gross tumor volume (GTV) + reproducibility of the patient’s self-breath-hold + 5mm safety margin. 4)Port margin around PTV 5mm in the protocol of 48Gy/4fr 0mm in the protocol of 60Gy/10fr and 70Gy/10fr 5)Beams: 6MV-X ray, non-coplanar multiple (>6) static ports or multiple (>400 degrees) dynamic arcs 6)Calculation algorithm: Clarkson or Convolution 7)Heterogeneity correction (+)

8. The treatment procedure In every fraction 1)Reassurance of reproducibility of patients’ self-breath-holds 2)Adjustment of the isocenter of the PTV to the planned position using CT- linac system under patients’ self-judged breath hold according to a respiratory indicator (ABCHES). 3)Irradiation performed under patients’ self-breath-holds 4)The tumor position in the irradiation port during irradiation was monitored with a real-time electronic portal imaging device (EPID) 5)The tumor position was verified using CT just after irradiation 【 CT 】 【 Symptom (pain) 】 2223366666 111111333333333333 SBRT Following up examination ( months after SBRT)

9. Analysis ①Time duration to detection of rib fracture ②Clinical symptom (pain) ③Comparison between cases with fracture (+) versus (-) a. Distance between tumor and chest wall b. Patient characteristics c. CT findings of chest wall d. Maximum dose of the rib

10. Results  Positive rib fracture (+) ： 41 cases  No rib fracture (-) for more than 24 months until the last follow-up : 46 cases 40Gy / 4 fr / 4-7 days 48 Gy / 4 fr / 4-7 days 60 Gy / 10 fr / 5-8 days 70 Gy / 10 fr / 5-8 days T1 T2 Fracture (+)Fracture (-) 0 / 1 (0.0%) 16 / 37 (43.2%) 14 / 34 (41.2%) 11 / 15 (73.3%) 25 / 61 (41.0%) 16 / 26 (61.5%) 1 / 1 (100.0%) 21 / 37 (56.8%) 20 / 34 (58.8%) 4 / 15 (26.7%) 36 / 61 (59.0%) 10 / 26 38.5%)

11. Time duration from SRT to detection of rib fracture Median : 15 months Mean : 16.8 months Cases number Time duration (months)

12. Pain*Fractute (+)(n=41)Fracture (-)(n=46) Grade 027/41(65.9%)39/46(84.8%) Grade 17/41(17.1%)4/46(8.7%) Grade 27/41(17.1%)3/46(7.7%) Grade 30/41(0%)0/46(0%) *CTCAE(Common Terminology Criteria for Adverse Events) v3.0 Clinical symptom (pain )

13. Distance between tumor and chest wall (mm) 16mm Fracture (-)Fracture (+) Comparison between cases with fracture (+) versus (-) Distance between tumor and chest wall

14. Fracture (+)(n=41)Fracture(-)(n=46) Age Mean 76.9 (64-89) Mean78.5 (61-91) Gender ＊ male: female 24 : 1736 : 10 ＊ p < 0.05 (chi-square test) Comparison between cases with fracture (+) versus (-) Patient characteristics

15. Fracture (+) (n=41)Fracture (-) (n=46) Chest wall edema 35(85.4%)10(21.7%) Thinning or erosion of the rib 30(73.2%)6(13.0%) Comparison between cases with fracture (+) versus (-) CT findings

16. Case 24 カ月後 86 y.o. female adenoca,T2N0M0 70Gy/10fr 24 months after 6 months after Chest wall edema and thinning of rib cortex Rib fracture

17. Risk factor* for rib fracture Odds ratio 95% confidential interval Age1.0280.929-1.138 Gender(Female)4.8621.135-20.819 Distance between tumor and chest wall 0.7820.696-0.879 * Stepwise Logistic regression anlysis

18. Fracture (+)(n=9)Fracture (-)(n=8) Maximum chest wall dose (BED Gy) 257.6 ± 48.2141.0 ± 76.1 Comparison between cases with fracture (+) versus (-) Maximum dose in chest wall ( in 17 cases in which detailed dose was calculated) ＊ ＊  = 3 Gy p<0.01 t-test

19. Fracture (+) (BED Gy) Comparison between cases with fracture (+) versus (-) Maximum chest wall dose (BED)  = 3 Gy Fracture (-)

20. ROC analysis Chest wall maximum BED ＝ 225.5Gy Sensiivity ＝ 0.71 1-Specificity= 0.11 Sensitivity (1-specificity) Comparison between cases with fracture (+) versus (-) Maximum chest wall dose (BED)

21. Fracture (-) Fracture (+) (Gy) 225.5Gy Likelihood ration=sensitivity/ (1-specificity ）＝ 0.71/0.11=6.45 Comparison between cases with fracture (+) versus (-) Maximum chest wall dose (BED)

22. 1.J. Thorac Oncol 2009:4:1035-37. 2.Int J Radiat Oncol Biol Phys 2010; 76:796-801. 3.Radiotherapy and Oncology 2009;91:360-68. 4.Lung Cancer 2005;48:107-14. 5.Lung Cancer 2008;60:193-9. 6.Lung Cancer 2006;51:97-103. Author Total Dose (Gy) High risk factors Voloney(1) Dunlap(2) Pettersson(3) Zimmermann4) Fritz(5) Nyman(6) 3 3 - 5 3 3 – 5 1 3 Distance to chest wall < 2cm, Median dose = 46.4Gy /3fr Chest wall volume receiving > 30Gy 2mL of rib received > 40Gy not demonstrated 9 (21.4%) 5 (8.3%) 7 (10.3%) 1 (3 %) 2 (5 %) 4 (8.9%) Fractions number No. of patients 42 60 68 30 40 45 54-60 21-60 45 24 - 37.5 30 45 Chest wall complications including rib fracture in previous literatures Rib fracture

23. Conclusion  Rib fracture after SBRT for lung cancer was produced in 41 of 177 cases (23.2%).  Female and short distance between the tumor and the chest wall were risk factors for production of rib fracture.  The distance between the tumor and the chest wall was under 16mm in all rib fracture cases.  Maximum BED(  =3Gy) of the chest wall in all rib fracture cases was over 200Gy