Frequency distribution of chemotherapy regimens
The frequencies of the chemotherapy regimens applied in this study are shown in table 4. The regimens include regimen A (composed of Vincristine, CCNU and Cisplatin) and regimen B (composed of Irinotecan, Temozolomide, Bevacizumab and Vincristine). Moreover, patients who received none of the above are shown with W and those who received both regimens sequentially are labeled as AB. Also, patients who received a regimen else than A at first and then received regimen B are labeled as WB. Regimen A has the highest regimen frequency while WB has the lowest one.
According to McDonald criterion11 (see supporting information, supplemental table 1), we categorized frequency and response rate of regimens in studied tumor into 5 groups based on MRI reports (table 5). With due attention to table 5, the most obvious response observed was complete response(CR) and minor response(MR) had the lowest prevalence amongst patients.
Progression free survival (PFS) was 55% in patients who have received salvage regimen after standard regimen (AB) and 38.5% in patients who received salvage regimen from the beginning(B). Although PFS is quite different in these two groups, this difference is not statistically significant (See table 6).
We also studied 6-month PFS in patients receiving salvage regimen based on their tumor type. Patients who had embryonal tumors and astrocytic tumors respectively had the longest and the shortest survival (see supporting information, supplemental table 2).
The PFS is 60% in male and 41.7% in female patients. Although there is a remarkably higher PFS in males than females, there is no meaningful relationship between 6-mon-PFS and sex (see supporting information, supplemental table 3).
Patients who received the salvage regimen after treatment with standard regimen (AB) depicted a higher survival rate in comparison with the other two groups. However, after survival analysis through the Kaplan-Meier procedure, there was no statistically significant correlation between survival and type of salvage regimen (Log Rank P-value=0.087). In addition, other factors previously proved to affect survival in children with primary brain tumor, such as age, sex and tumor type were analyzed with the Kaplan-Meier procedure to inspect their effect on patients’ survival during the course of treatment (see supporting information, supplemental table 4).
There was no significant relationship between age and survival despite adolescent and infant 2-year survivals being higher than other age groups. Although survival rate for females was higher than males (1.838 and 1.700), this difference was not of statistical significance. Patients with ependymomal tumors had the longest estimated survival time (2 years) and the highest survival rate (90%). Nevertheless, tumor type was not meaningfully correlated with survival (see supporting information, supplemental tables 5,6 and 7).
Conclusion and discussion
Once again, as we already mentioned in previous sections, the incidence of brain tumors is higher in males (60%) than in females (40%). This fact can also be observed in different subdivisions of brain tumors as in that embryonal and ependymomal tumors are more prevalent in males than females. However, astrocytic tumors have an almost similar occurrence in both sexes. The dominance of brain tumor incidence in males compared to females is a recognized fact in which factors such as the role of sex hormones and sex chromosomes are highly important.18
The analysis of the collected data in this study showed that the incidence of pediatric brain tumors is highest in child (6_12) and young child (2_6) age group, with a peak in the average age of 6.5 years old. This finding is compatible with the findings of Golshani et. all study conducted in 1997_2015.10The most prevalent primary brain tumors were embryonal (especially medulloblastoma) and astrocytoma (especially low-grade glioma), acknowledging the findings of Wells’ et all study.8
Infratentorial tumors are more prevalent in comparison with supratentorial and spinal tumors especially in children below the age of 12. This is compatible with the findings of Gottardo et all in 2008.5
However, this study also showed that supratentorial tumors are more common in the infant age group, which is in contrast with Gottardo’s findings.5The most prevalent initial manifestations of brain tumors, with respect to their frequency percentage, were : headache(31.7%),vomiting(26.2%),ataxia(12.7%) and double vision(5.6%). In a similar study conducted by Zali et all, vomiting, headache and ataxia were respectively the most prevalent initial symptoms. In another metanalysis carried out by Wilen et all, headache, vomiting and ataxia were sequentially the most prevalent symptoms. This high incidence of the three mentioned symptoms could be related to the increased intracranial pressure with a precise focus on the cerebellum, a part of the brain that has a key role in regulating balance and voluntary movement.4
In the current study, out of 88 patients with pediatric brain tumors, 38 persons received the Irinotecan based lifesaving regimen, 8 of which had embryonal tumors, 20 had Astrocytic and 10 had ependymomal tumors. The remaining 50 patients received either other standard regimens or a non-Irinotecan containing regimen. The medical responses of those 38 patients were recorded and investigated.
Out of the 38 patients mentioned above, 23 received the lifesaving regimen due to a lack of response to other standard regimens (20 received AB and 3 received WB regimen) and the other 15 patients received the lifesaving regimen( regimen B) from the beginning due to the inoperability of the tumor or its histological nature and its high grade of invasiveness. Half of those who received the AB regimen had an ependymomal tumor while the other half suffered Astrocytic or embryonal tumors. Of the 15 patients who received regimen B, 13 patients suffered Astrocytic tumors, a majority of which were DPG and HGG tumors.
Ultimately, among the 20 patients who received AB regimen, PFS was 55% with a SE of 11.1 while in the 15 patients who received regimen B from the beginning PFS at the end of 6 months was 38.5% with a SE of 13.5. The reason behind a lower OS and PFS in patients who received B regimen compared to those who received AB, is the high-grade nature of Glioma tumors and their highly risky location near the brainstem. In this case, Vredenburg et all came up with similar conclusions in a study conducted between January and December 2007.14,19
In a study conducted by Hummel Trent et all between the years 2000 and 2013, 27 patients of whom, 15 had DIPG and 12 had HGG, with an average age of 10-year-old were studied. Patients received Bevacizumab, Irinotecan and Temozolomide either due to an inadequate response to other standard chemotherapy regimens or due to relapse. Conclusively, three-year PFS and OS were respectively 33% and 50%, which are similar results to the findings of the current study.20
In another study conducted by Zhang et all during the years 2000_2011, 480 patients with Glioblastoma multiforme (GBM) were studied. 183 patients received only a Bevacizumab containing regimen while the others (397 patients) received a combination of Bevacizumab and Irinotecan. The average OS for the first group (only Bevacizumab) was 8.63 months and 8.91 for the second group (Bevacizumab and Irinotecan combination). Although the results of Zhang’s study were similar to the current study, adding Irinotecan to the Bevacizumab regimen didn’t make a statistically significant difference in the 6_month PFS and OS.21
The findings of this study suggest that embryonal tumors have an average PFS and OS of 62.5% while ependymomal tumors have a PFS of 60% and an OS of 90%. Furthermore, Astrocytic tumors have a PFS of 47.4% and an OS of 65%, which is compatible with the suggested PFS for high grade Astrocytic tumors (38%) in Parekh et all study.22
In this cross-sectional study, 8 patients with relapsing medulloblastoma received the AB regimen and 2 patients received B regimen from the beginning, all of whom had an average PFS and OS of 62.5% which is the highest OS among all three major tumor subdivisions. This is compatible with the findings of Aguilera et all study and suggests that the combination of Bevacizumab and Irinotecan, with or without Temozolomide, provides the most effective response with the lowest toxicity in children with relapsing medulloblastoma .23
However, when Grill et all conducted a research in 2013 in which they studied 66 patients with treatment resistant medulloblastoma and applied Temozolomide and Irinotecan regimens, an average PFS of only 37% was recorded. This does not match with the findings of this study.24
Patients who received the AB regimen following an application of standard regimens had a higher PFS and OS (55% and 85%), compared with those who received the B regimen from the very beginning (38.5% and 50%). Nevertheless, this difference was not statistically significant, matching the findings of Vredenburgh et all study.14
Research limitations: 1. Deficiencies in medical records to which a better dedication is required  2. Patients’ not referring to the hospital for further evaluations, so that contacting them through phone calls was a necessity 3. Difficult access to radiology series and surgical records 4. A necessity for further research and investigations, considering the growing incidence of primary pediatric brain tumors and lack of information in its respective field