1. Comparison of SIB-IMRT and Conventional Accelerated Hyper-fractionated IMRT With Concurrent Cisplatin and Etoposide for Limited Disease SCLC Baosheng Li M.D. Ph.D. Shandong Cancer Hospital, Department of Radiation Oncology

2. Disclosure No conflict of interests to disclosure

3. Background  At the time of diagnosis, 30%-40% of SCLC patients present with limited disease (LD).  SCLC is characterized by a rapid doubling time,high growth fraction, and early development of widespread metastases.  Patients with disease in excess of T1-2, N0 do not benefit from surgery.  Concurrent chemoradiotherapy represents the standard treatment for patients with LD-SCLC.

4. Background  Accelerated hyper-fractionated radiotherapy (45Gy with 1.5Gy twice daily in 3 weeks)  Dose-escalated conventional radiotherapy (60- 70Gy with 2Gy once daily in 6 to 7 weeks )  Concurrent chemoradiotherapy have been documented as reliable schedules.

5. RT in SCLC  53.6%±3.3% SCLC patients need RT in every stage in the disease  45.4%±4.3% SCLC patients in the initial treatment  8.2%±1.5% SCLC patients later for recurrence or progression  Local failures occur in approximately one third of patients and the outcome is still poor.

6. RTOG 97-12 Komaki R, et al. IJROBP. 62,342-350, 2005

7. Lg Field (1.8 Gy/Fx) Boost (1.8Gy Bid) Total Dose x (off cord) RTOG 97-12 Wk 1 2 3 4 5

8. RTOG 0239  RT compliance rate: 95 %  Objective response: CR: 41%, PR: 39%  2Y OS: 36.6 % Severe hematopoietic toxicity was as high as 90% ( 15 grade 3 and 49 grade 4).

9. Protocol:  6 cycles of etoposide and cisplatin.  Cycles 4 and 5 included concurrent higher dose TRT (30Gy/20 twice daily fractions, a 2-week break, and another 30Gy/20 twice daily fractions). NCCTG 95-20-53 Schild SE,et al. J Clin Oncol 2007, 25: 3124-3129.

10. Results  A total of 76 assessable patients enrolled.  5-year OS rate: 24%.  The locoregional failure remained a problem and grade 3 or grade (3+) toxicities were as high as 97%.

11. Phase III trial of concurrent thoracic radiotherapy with either first- or third-cycle chemotherapy for limited- disease small-cell lung cancer Sun jm,et al. Ann Oncol. 2013;24(8):2088-92

12.  Results: 222 patients were randomly assigned early TRT Late TRT P-value CR 36% 38% >0.05 Median OS 24.1 26.8 >0.05 Median PFS 12.4 11.2 >0.05 Meutropenic fever 21.6% 10.2% 0.02  Conclusion: TRT starting in the third cycle of chemotherapy seemed to be noninferior to early TRT, and had a more favorable profile with regard to neutropenic fever.

13. Our retrospective study was to compare toxicities, disease control and survival outcomes for LD-SCLC treated with simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) versus conventional accelerated hyper-fractionated radiotherapy. Purpose

14. METHODS

15. Group A Group B Total P*P*P*P* Number of patients 4357100 Age (years) 0.078 median555756 range35-7240-7435-74 ECOG PS 0.460 0-1415192 2268 Gender 0.130 M294675 F141125 AJCC 7 stage 0.940 Ⅰ112 Ⅱ5811 ⅢAⅢAⅢAⅢA142731 ⅢBⅢBⅢBⅢB152129 Patient Characteristics

16. Chemotherapy  Two cycles chemotherapy before TRT with EP regimen (etoposide 100mg/m2 day 1-5, and cisplatin 25mg/m2 day 1-3, 21 days per cycle) were delivered.  Then adjuvant chemotherapy were administered after completion of thoracic radiotherapy. Chemotherapy was administered every 3 weeks.  A total of 4-6 cycles were administered.

17.  GTV: including the residual primary tumor and involved lymph nodes after induction chemotherapy. TDF: 1.9Gy/f @ 30f in 3 weeks, 5 days a week.  CTV: defined by expanding GTV with a 0.5 cm margin and involved lymph node region. TDF: 1.7Gy/f @ 30f in 3 weeks, 5 days a week.  PTV: defined by expanding CTV with a 0.5 cm margin. TDF: 1.5Gy/f @ 30f in 3 weeks, 5 days a week. SIB-IMRT protocols

18. SIB-IMRT

19.  The targets were defined as the same as SIB-IMRT.  TDF:1.5Gy/f @ 30f in 3 weeks, 5 days a week to PTV. Conventional Accelerated Hyper-fractionated Radiotherapy Protocols

20.  Lung ： mean lung dose < 20Gy, lung V20 < 33% ；  spinal cord : Dmax≤41Gy;  Heart ： mean heart dose < 30Gy ， V40<46% ；  Esophagus ： mean esophagus dose < 34 Gy, V35 < 50%. Organs at risk

21.  Patients who achieved CR or nCR were administered PCI (25 Gy in 10 fractions to the entire brain) within 4 weeks after completion of all chemotherapy. Prophylactic cranial irradiation

22. Results

23. Group AGroup B mean ± SD P*P* MLD(Gy) a 17.7 ± 10.314.8 ± 1.70.099 V5(%) b 67.4 ± 9.066.4 ± 9.80.678 V15(%) b 37.8 ± 5.836.3 ± 7.80.188 V20(%) b 28.7 ± 3.224.5 ± 4.60.272 V25(%) b 20.8 ± 4.419.0 ± 3.80.604 V30(%) b 17.1 ± 2.614.1 ± 2.61.000 V35(%) b 12.6 ± 3.511.3 ± 2.80.534 Ipsilateral lungs MLD(Gy)22.1 ± 4.120.9 ± 3.50.564 V5(%)79.1 ± 10.779.1 ± 11.70.941 V15(%)61.1 ± 11.761.2 ± 10.70.633 V20(%)47.2 ± 11.345.6 ± 9.30.536 V25(%)37.7 ± 11.234.3 ± 8.80.472 V30(%)30.3 ± 10.027.7 ± 8.50.761 V35(%)24.1 ± 8.622.0 ± 10.10.717 Contralateral lungs MLD(Gy)8.8 ± 2.98.1 ± 2.90.773 V5(%)53.1 ± 13.155.0 ± 12.80.962 V15(%)18.6 ± 10.115.8 ± 11.60.748 Total lungs

24. V20(%)11.8 ± 8.87.3 ± 7.30.567 V25(%)7.2 ± 5.54.5 ± 4.80.512 V30(%)5.2 ± 4.63.3 ± 3.60.457 V35(%)3.6 ± 3.42.2 ± 2.50.415 Spinal cord Dmax(Gy) e 42.7 ± 3.741.0 ± 1.20.090 Heart Dmean(Gy) a 16.1 ± 7.315.0 ± 7.20.641 V30(%) c 23.3 ± 15.018.1 ± 11.40.253 V40(%) c 9.0 ± 5.06.7 ± 3.80.342 Esophagus MED(Gy) a 29.0 ± 6.726.8 ± 5.50.575 V45(%) d 33.6 ± 5.333.0 ± 4.50.882

25. Toxicity Grade A组A组 B组B组 TotalP* Hematologic toxicit （ WBC ） ≥2 38 (88%) 30 (53%) 68 (68%)<0.001 Hematologic toxicity （ PLT ） ≥2 9 (21%) 9 (16%) 18 (18%)0.508 Hematologic toxicity （ HB ） ≥2 11 (26%) 11 (19%) 22 (22%)0.453 Stomach/intestine ≥2 16 (37%) 12 (21%) 28 (28%)0.075 Esophagitis ≥2 23 (53%) 26 (46%) 49 (49%)0.435 Pneumonitis ≥2 5 (11%) 3 (5%) 8 (8%)0.284

26. Treatment response ResultsGroup A N = 43 Group B N = 57 P* 0.953 Response Complete response22 (51%)28 (49%) Partical response16 (37%)20 (36%) Near complete response5 (11%)5 (8%) Total38 (88%)48 (85%) Stable disease4 (9%)6 (10%) Progressive disease1 (3%) 3 (5%)

27. Survival Outcome measureGroup AGroup BP* Overall survival 0.165 Median duration32months28months 2 Years70.2%55.2% 3 Years46.3%36.2% Progression-free survival 0.077 Median duration22.5months15.5monts 2 Years45.7%35.9% 3 Years30.1%18.6% Locoregional recurrence-free survival 0.093 Median duration31.5months23monts 2 Years67.3%46.8% 3 Years34.9%26.3%

28. OS OS P = 0.165

29. PFS P = 0.077

30. LRFS P = 0.093

31. Conclusions  Comparing with conventional accelerated hyper- fractionated RT, SIB-IMRT for limited Disease SCLC was feasible and had the potency of improving local regional recurrence. However, the toxicity was still higher.

32. Acknowledgements Dr. Dan Han Dr. Tao Zhou Dr. Zhongtang Wang Dr. Hongsheng Li Prof. Yong Yin Associate Prof. Jian zhu

33. Thank you !