1. Possibility of craniospinal irradiation dose reduction for children with metastatic medulloblastoma
(PROS 2019 Meeting, Bangkok, June 19-22)
V.A. Grigorenko1, A.S. Levashov1, I.V. Glekov1, A.M. Stroganova1, D.A. Khochenkov1, M.V. Ryzhova2, S.K. Gorelyshev2, S.S. Babelyan1, N.N. Subbotina1, V.V. Daylidite1, S.R. Zagidullina1, I.S. Dolgopolov, G.L. Mentkevich1
1 N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe shosse, 24, Moscow, Russia,
2 N.N. Burdenko National Medical Research Center of Neurosurgery, 4th Tverskaya-Yamskaya 16, Moscow, Russia,
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 iso17q.
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 2D technology, from 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 6q21/MYC(8q24) probe, MYC(8q24) SE8 control probe, N-MYC gene amplification – NMYC(2p24)/ LAF(2q11), iso17q – TP53(17p13)/MPO(17q22).
Results
All patients were included in HRG. Male / female ratio was 1.4 / 2, all patients was older 3 years of age. R1 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, Iso17q – 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 ± 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 ± 10.4% at mean survival time of 49.3 ± 9.6, 57.7 ± 8.6 months (Figure 4). DFS of patients with MYC/N-MYC and/or Iso17q – positive tumor samples was 20.1 ± 12.2%, other ± 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 NeuroCHOI , 31.3 ± 24.2% in NeuroCHOI 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 NeuroCHOI , 17 in NeuroCHOI (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
Therapeutic program
Total (%)
Neuro - CHOI
2008 – 2014
(%)
Neuro – CHOI 2014 – 2018
Individual treatment program
(2008 – 2018) p
Arm A (%)
Arm B (%)
Arm C (%)
Number of patients
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)
8 (88.9)
1 (11.1)
0,724
R1 (%)
28 (52.8)
7 (50.0)
1 (14.3)
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 (%)
23 (43.4)
12 (70.6)
0,255
Consolidation therapy
Chemotherapy
HD chemotherapy
HD chemotherapy + 5-AZA
30 (88.7)
1 (1.9)
16 (43.4)
17 (100)
9 (53)
2 (33.3)
3 (33.3)
Histological variant
Classic
Large cell-anaplastic
47 (88.7)
6 (12.3)
13 (92.9)
1 (7.1)
6 (85.7)
5 (83.3)
1 (16.7)
0,519
Number of samples
Negative samples
C-MYC gain.
C-MYC amplification
N-MYC gain.
N-MYC amplification
Iso17q
С-MYC ampl./Iso17q
N-MYC ampl./Iso17q
N-MYC gain./Iso17q
C-MYC gain./Iso17q
41 (100)
15 (36.7)
1 (2.4)
3 (7.3)
2 (4.9)
16 (39) 8 3 1 4 7 16 2 5
0,532
Events:
Progression
Early relapse
Late relapse
Local relapse
Disseminated relapsed
TRM:
Fatal septic complication
Fatal non – septic complication
29 (54.7) 9
8 (15.1)
9 (64.3)
3 (42.9)
6 (35.3)
7 (77.8)
0,225
0,145
0,704
Figure 1. Treatment protocols
Neuro CHOI 2008 – 2014
(Like – SJMB 03)
Neuro CHOI 2014 – 2018
Arm A
Arm B
Arm C
Surgery
Stem cell harvest
Induction chemotherapy
OPEC
OPEC ± HD MTX
(1 or 2 cycles)
Craniospinal irradiation 36 Gy
Local irradiation up to 54 Gy, daily fraction 1.8 Gy
Craniospinal irradiation 23.4 Gy, daily fraction 1.8 Gy
Craniospinal irradiation 23.4 (for CR after induction CT), other 36 Gy; Local irradiation up to 54 Gy, daily fraction 1.8 Gy ± 5-AZA
Craniospinal irradiation 23.4 Gy, daily fraction 1.8 Gy; + vincristin / carboplatin
HD chemotherapy with auto stem cell rescue
HD cyclophosphamide – based regimen (4 cycles)
HD chemotherapy with auto stem cell transplantation (Thiophosphamide / carboplatin + 5-AZA)
(2 cycles)
HD chemotherapy with auto stem cell transplantation (Thiophosphamide / carboplatin)
HD chemotherapy with auto stem cell transplantation (Thiophospamide / carboplatin)
OPEC – vincristine, cisplatin, etoposide, cyclophosphamide; 5-AZA – 5-azacitidine; HD – MTX – high dose methotrexate
Disease - free survival
Disease - free survival
Age: 6 years and older,
n = 26, events = 11
n = 45, events = 20
Age: 4 – 5 years,
n = 7, events = 5
p = 0.740
Months
Months
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 Iso17q negative tumor samples.
Figure 3. Disease–free survival,
4 – 5 years of age / 6 and more
(Group with 36 Gy CSI)
Figure 2. Disease-free survival in the whole children's group
Other, n = 15, events = 4
CSI 23.4 Gy, n = 12, events = 4
Disease - free survival
Disease - free survival
Neuro CHOI 2008 – 2014,
n = 13, events = 8
Disease - free survival
Individual program,
n = 7, events = 4
CSI 36 Gy, n = 33, events = 16
Neuro CHOI ,
n = 13, events = 4
C-MYC, N-MYC ampl./gain and/or Iso17q, , n = 21, events = 11
p = 0.359
p = 0.471
p = 0.506
We thank the Khabensky Charitable Foundation which supported this work and organized a visit of our expert to the conference!
Months
Months
Months
Figure 4. Disease-free survival according to CSI dose
Figure 5. Disease–free survival according to
C-MYC, N-MYC ampl./gain or Iso17q tumor status
Figure 6. Disease–free survival according to therapeutic program
(Group with 36 Gy CSI)