Possibility of craniospinal irradiation dose reduction for children

Possibility of craniospinal irradiation dose reduction for children with metastatic medulloblastoma (PROS 2019 Meeting, Bangkok, June 19 -22) V. A. Grigorenko 1, A. S. Levashov 1, I. V. Glekov 1, A. M. Stroganova 1, D. A. Khochenkov 1, M. V. Ryzhova 2, S. K. Gorelyshev 2, S. S. Babelyan 1, N. N. Subbotina 1, V. V. Daylidite 1, S. R. Zagidullina 1, I. S. Dolgopolov, G. L. Mentkevich 1 1 N. N. Blokhin National Medical Research Center of Oncology, Kashirskoe shosse, 24, Moscow, Russia, 115478 2 N. N. Burdenko National Medical Research Center of Neurosurgery, 4 th Tverskaya-Yamskaya 16, Moscow, Russia, 125047 Aim The aim of this study was estimating of disease-free survival (DFS) according to craniospinal irradiation dose (CSI), presence of MYC/N-MYC gene gain/amplification or iso 17 q. Design and methods From 2008 to 2018 fifty three pediatric patients with de novo metastatic medulloblastoma were included in trial. Treatment program was presented in Figure 1. From 2008 to 2014 radiation therapy was carried out using 2 D technology, from 2014 - modern linear electron accelerators with IMRT technique were used. The number of isocenters ranged from 2 to 4. Fixation was carried out using a thermoplastic mask, a vacuum mattress. The verification of the plan was carried out using CBCT for the first 3 days, then once a week. If necessary, the treatment was carried out with an anesthetic management. Radiation daily dose was 1. 8 Gy. 15 patients were treated with 23. 4 Gy CSI dose and 38 patients - 36 Gy. 23 Gy CSI was used for all patients in Arm A, for patients with complete response after induction chemotherapy in Arm B and for all patients in Arm C simultaneously with chemotherapy. Local exposure was continued up to 54 Gy. The C-MYC gene amplification was assessed by FISH using 6 q 21/MYC(8 q 24) probe, MYC(8 q 24) SE 8 control probe, N-MYC gene amplification – NMYC(2 p 24)/ LAF(2 q 11), iso 17 q – TP 53(17 p 13)/MPO(17 q 22). Results All patients were included in HRG. Male / female ratio was 1. 4 / 2, all patients was older 3 years of age. R 1 status was revealed in 28 patients, M+ – in 53 (100%), large cell anaplastic histological variant - in 6 (12. 3%). MYC/N-MYC gene gain/amplification were revealed in 10 (24. 4%) out of 41 samples, Iso 17 q – in 20 out of 41 (48. 8%) (Table 1). DFS for all patients was 37. 5 ± 9. 6 % at mean survival time of 61. 4 ± 8. 6 months and median follow-up 46. 3 ± 5. 9 months (Figure 2). DFS for children 4 -5 years old was 28. 6 ± 17. 1, for children 6 years and older - 35. 4 ± 12. 8 at mean survival time of 51. 1 ± 16. 8, 58. 9 ± 11. 7 months (Figure 3). DFS for children who were treated of 23. 4 Gy was 56. 2 ± 18. 7%. , CSI 36. 0 Gy - 33. 3 ± 10. 4% at mean survival time of 49. 3 ± 9. 6, 57. 7 ± 8. 6 months (Figure 4). DFS of patients with MYC/NMYC and/or Iso 17 q – positive tumor samples was 20. 1 ± 12. 2%, other - 61. 0 ± 16. 8% at mean survival time of 40. 7 ± 6. 2, 77. 2 ± 15. 6 months (Figure 5). DFS for patients who were treated of 36 Gy CSI was 38. 5 ± 13. 5% in Neuro. CHOI 2008 -2014, 31. 3 ± 24. 2% in Neuro. CHOI 2014 -2018 and 42. 9 ± 18. 7% in Individual treatment program at mean survival time of 66. 5 ± 12. 1, 31. 3 ± 5. 9, 32. 8 ± 10. 0 months (Figure 6). 8 events were revealed in Neuro. CHOI 2008 -2014, 17 in Neuro. CHOI 2014 -2018 (7 in arm A, 6 in arm B, 4 in arm C), 7 in individual treatment program (p = 0. 532). Events were presented by: late relapse in 7 cases, early relapse in 7 cases, progression in 7 cases. Arm A and C were prematurely completed due to high toxicity (arm A – grade 3 and 4 gastrointestinal toxicity after HDCT, arm C – grade 3 and 4 hematological toxicity and neurotoxocity). Treatment related mortality was 15, 1% (8 children, 5 due to septic complications, 3 – other toxicity). Table 1. Patients and tumor samples characteristics according to treatment program Figure 1. Treatment protocols Neuro CHOI 2008 – 2014 (Like – SJMB 03) Neuro CHOI 2014 – 2018 Therapeutic program Stem cell harvest Arm A Arm B Arm C Surgery Induction chemotherapy OPEC Stem cell harvest Induction chemotherapy OPEC ± HD MTX Stem cell harvest (1 or 2 cycles) Craniospinal irradiation 23. 4 Gy, daily fraction 23. 4 (for CR after 23. 4 Gy, daily fraction 1. 8 Gy induction CT), other 36 1. 8 Gy; + vincristin / Gy; Local irradiation up carboplatin to 54 Gy, daily fraction 1. 8 Gy ± 5 -AZA HD chemotherapy with auto stem cell HD chemotherapy with rescue auto stem cell HD cyclophosphamide – based transplantation regimen (4 cycles) (Thiophosphamide / (Thiophospamide / carboplatin + 5 -AZA) carboplatin) (2 cycles) Local irradiation up to 54 Gy, daily fraction 1. 8 Gy n = 45, events = 20 Disease - free survival OPEC – vincristine, cisplatin, etoposide, cyclophosphamide; 5 -AZA – 5 -azacitidine; HD – MTX – high dose methotrexate Age: 6 years and older, n = 26, events = 11 Age: 4 – 5 years, n = 7, events = 5 p = 0. 740 Months Figure 3. Disease–free survival, 4 – 5 years of age / 6 and more (Group with 36 Gy CSI) CSI 23. 4 Gy, n = 12, events = 4 CSI 36 Gy, n = 33, events = 16 Disease - free survival Figure 2. Disease-free survival in the whole children's group Other, n = 15, events = 4 C-MYC, N-MYC ampl. /gain and/or Iso 17 q, , n = 21, events = 11 p = 0. 506 Months Figure 4. Disease-free survival according to CSI dose Total (%) Figure 5. Disease–free survival according to C-MYC, N-MYC ampl. /gain or Iso 17 q tumor status Arm A (%) Arm B (%) Arm C (%) p 53 (100) 14 (26. 4) 7 (13. 2) 17 (32. 1) 6 (11. 3) 9 (17. 0) Sex: Male Female 31 (58. 5) 22 (41. 5) 8 (57. 1) 6 (42. 9) 5 (71. 4) 2 (28. 6) 10 (58. 8) 7 (41. 2) 3 (50. 0) 5 (55. 6) 4 (44. 4) 0, 948 Age: 6 and older 4 -5 41 (77. 4) 12 (22. 6) 10 (71. 4) 4 (28. 6) 6 (85. 7%) 1 (14. 3%) 14 (82. 4) 3 (17. 6) 3 (50. 0) 8 (88. 9) 1 (11. 1) 0, 724 R 1 (%) 28 (52. 8) 7 (50. 0) 1 (14. 3) 10 (58. 8) 4 (66. 7) 6 (66. 7) 0, 182 Craniospinal irradiation 23. 4 Gy 36. 0 Gy 15 (28. 3) 38 (71. 7) 14 (100) 7 (100) - 2 (11. 8) 15 (88. 2) 6 (100) - 9 (100) 0, 647 Local irradiation up to 54 Gy + 5 – AZA (%) 0, 255 23 (43. 4) - 7 (100) 12 (70. 6) - 4 (44. 4) Consolidation therapy Chemotherapy HD chemotherapy + 5 -AZA 30 (88. 7) 1 (1. 9) 23 (43. 4) 16 (43. 4) 14 (100) - 7 (100) 17 (100) 9 (53) 17 (100) - 2 (33. 3) - 9 (100) 5 (55. 6) 3 (33. 3) 4 (44. 4) Histological variant Classic Large cell-anaplastic 47 (88. 7) 6 (12. 3) 13 (92. 9) 1 (7. 1) 6 (85. 7) 1 (14. 3) 14 (82. 4) 3 (17. 6) 5 (83. 3) 1 (16. 7) 9 (100) - 0, 519 Number of samples Negative samples C-MYC gain. C-MYC amplification N-MYC gain. N-MYC amplification Iso 17 q С-MYC ampl. /Iso 17 q N-MYC gain. /Iso 17 q C-MYC gain. /Iso 17 q 41 (100) 15 (36. 7) 1 (2. 4) 3 (7. 3) 2 (4. 9) 16 (39) 2 (4. 9) 1 (2. 4) - 8 3 1 4 - 7 3 1 3 - 16 7 1 2 5 1 - 2 1 1 - 8 2 1 3 1 1 - 0, 532 Events: Progression Early relapse Late relapse Local relapse Disseminated relapsed TRM: Fatal septic complication Fatal non – septic complication 29 (54. 7) 7 7 7 5 9 8 (15. 1) 5 3 9 (64. 3) 0 3 5 4 4 1 1 0 3 (42. 9) 0 1 1 0 2 1 1 0 6 (35. 3) 2 1 1 0 2 2 1 1 4 (66. 7) 2 0 0 2 1 1 7 (77. 8) 3 2 0 1 1 2 1 1 0, 225 0, 145 0, 704 Conclusion. Treatment program intensification by using HDCT Thiophosphamide/carboplatine and combination of RT with CT allowed us to reduce CSI dose down to 23. 4 Gy for some children with M+ status and MYC/N-MYC and/or Iso 17 q negative tumor samples. Neuro CHOI 2008 – 2014, n = 13, events = 8 Individual program, n = 7, events = 4 Neuro CHOI 2014 - 2018, n = 13, events = 4 p = 0. 359 Months Neuro - CHOI 2008 – 2014 (%) Individual treatment program (2008 – 2018) Number of patients Disease - free survival Surgery Craniospinal irradiation 36 Gy Local irradiation up to 54 Gy, daily fraction 1. 8 Gy Neuro – CHOI 2014 – 2018 p = 0. 471 Months Figure 6. Disease–free survival according to therapeutic program (Group with 36 Gy CSI) We thank the Khabensky Charitable Foundation which supported this work and organized a visit of our expert to the conference!