Metastatic MB Patients
This research was carried out according to the ethics committee’s principles of Beijing Shijitan Hospital, and informed consent was obtained from children’s parents or their legal guardians.
During the period of October 1, 2012 through April 10, 2020, a total of 185 children, those with metastatic MB treated with chemotherapy and irradiation therapy after surgical resection were enrolled in this study. The median age was 6.8 years old (mean: 7.2 years, range: 0.2–16.6 years). Here, 111 patients were gross total resection (GTR), 60 were near total resection (NTR), 13 were subtotal resection (STR), and one was unable to be removed and had to be performed biopsy owning to the widespread of tumor cells in skull. Moreover, 115 patients were classic MB (CMB), 45 patients were desmoplastic/nodular and MB with extensive nodularity (DNMB and MBEN), and 23 patients were large-cell and anaplastic MB (LCAMB). As to the molecular subgroup, 57 cases were SHH, 27 cases were Group 3, 97 cases were Group 4, one case was WNT, and two cases were not otherwise specified (NOS).
Importantly, 42 patients were positive presence of tumor cells in CSF, and 39 cases were positive with MYC or TP53 aberrant. The characteristics of these gene aberrant patients were shown in Table 1.
Table 1 Demographics and disease characteristics of patients with MYC/TP53 aberrant
Parameters
|
Metastatic Patients (n=39)
|
Gender
Male
Female
|
28
11
|
Age at diagnosis (years)
Mean
Median (range)
|
5.4
4.9 (1.1–10.3)
|
Resection extent
GTR
NTR
STR
Only Biopsy
|
27
10
1
1
|
Histopathology subtype
CMB
DNMB
LCAMB
|
19
9
11
|
Molecular subgroup and MYC/TP53
SHH
MYC positive aberrant
TP53 positive mutation
MYC and TP53 positive aberrant
Group 3
MYC positive aberrant
TP53 positive mutation
Group 4
MYC positive aberrant
TP53 positive mutation
WNT
TP53 positive mutation
|
5
4
2
15
3
7
2
1
|
Tumor cells in CSF
Positive
Negative
|
20
19
|
Note: MB, medulloblastoma; CMB, classic medulloblastoma; DNMB, desmoplastic/nodular and medulloblastoma with extensive nodularity; LCAMB, large-cell and anaplastic MB; SHH, sonic hedgehog; CSF, cerebrospinal fluid; GTR, Gross total resection; NTR, near total resection; STR, subtotal resection.
In addition, among those MYC or TP53 positive aberrant patients, 6 cases were newly found MYC/TP53 aberrant in tumor cells of CSF, while not detected in surgical specimen. Meanwhile, MYC or TP53 aberrant were positive in 33 surgical specimens, and 14 cases were positive MYC or TP53 aberrant both in surgical specimens and CSF, 19 cases were positive only in surgical specimens (see Table 2).
Table 2 The status of MYC/TP53 aberrant of tumor cells in CSF or surgical specimen of patients with metastatic MB
|
MYC (+)
|
TP53 (+)
|
MYC and TP53 (+)
|
Total
|
Specimen (+) and CSF (-)
|
13
|
5
|
1
|
19
|
Specimen (+) and CSF (+)
|
10
|
3
|
1
|
14
|
Specimen (-) and CSF (+)
|
4
|
2
|
0
|
6
|
Total
|
27
|
10
|
2
|
39
|
Moreover, the MYC amplification was present in more than half of Group 3 MB (55.5%), while TP53 mutation was present in about 11.1%. The relationship between MYC/TP53 aberrant in CSF and surgical specimen was further described in Fig. 2.
Survival of patients
Of all these 185 patients, the median survival time was 2.3 years (range: 0.2–7.6 years), and the estimated 5-year PFS and OS rates were 48.1 ± 4.8% and 53.6 ± 5.3% (± standard error), respectively. However, the survival of patients with positive gene aberrant was very poor, and much lower than those of negative aberrant group (P<0.01). In fact, the median survival time of those patients with MYC/TP53 positive aberrant was only one year (range: 0.2–2.5 years), and all patients were nearly died in 2.5 years. The one- and 2-year PFS/OS rates of patients with positive gene aberrant were 15.4 ± 5.8% / 51.9 ± 8.3%, and 2.6± 2.5% / 11.5 ± 5.4%, respectively. On the other hand, the median survival time of patients with negative gene aberrant was 2.2 years (range: 0.3–7.6 years), and the one- and 2-year PFS/OS rates were 91.6 ± 2.3% / 95.9 ± 1.7%, and 77.0 ± 3.7% / 90.5 ± 2.6%, respectively (see Fig. 3A, 3B). Even the 5-year PFS/OS rates were 61.1 ± 5.6% / 68.3 ± 6.1%, respectively.
Risk factors associated with survival
Multivariate analysis using risk factors with Cox’s proportional hazard model showed that molecular group and presence of tumor cells in CSF were independent predictive factors for PFS in patients with metastasis (95% CI was 1.153-2.026 and 1.651-5.387, respectively, and P<0.05). Meanwhile, besides of molecular group and presence of tumor cells in CSF, positive gene aberrant was an independent risk factor associated with OS of metastatic patients (95% CI was 1.378-2.728, 2.145-8.165 and 0.266-0.998, respectively, and P<0.05).
Adverse effects
More than 70% of patients experienced gastrointestinal disorders, including anorexia, nausea and abdominal pain, etc. But all these disorders were controlled promptly using antiemetics or probiotics [13]. Various degrees of myelosuppression appeared in all patients. Six patients had to decrease their carboplatin and etoposide doses by 10% owing to myelosuppression, and 6 patients received red cell or platelet transfusions. No patients were withdrawn from the chemotherapy regimen due to adverse events.