Introduction

Brain stem tumors are one of the most malignant pediatric brain tumors [13, 22]. They account for 12.2 % of all pediatric brain tumors [22, 29]. Among all brain stem tumors, 80 % are diffuse intrinsic pontine gliomas (DIPG) [10, 19, 20]. Typical magnetic resonance imaging (MRI) findings and the impossibility to completely resect most tumors lead these patients to be treated without histological confirmation [2, 8]. Radiotherapy (RT) is known to extend survival and frequently improve the quality of life for a period of time [8]. A positive role of chemotherapy has been suggested in some retrospective analysis [28], but the effect appears to be small. After radiochemotherapy, these tumors shrink but recur rapidly. Survival outcome for this group of tumors are worse than any other CNS tumor. Median time until progression is 5–6 months, median survival time is usually less than 1 year, and survival beyond 2 years from diagnosis is less than 10 % [12, 14]. There seems to be no progress in the last 20 years [3–7, 9–11, 14–18, 21, 22, 26]. In this retrospective study, we documented the outcome and survival analysis of DIPG patients who received RT only and those who received RT and concomitant chemotherapy.

Materials and methods

We retrospectively reviewed a total of 50 DIPG patients treated at the Oncology Institute of Istanbul University from February 1999 to May 2012. During this period, a total of 512 pediatric patients with brain tumors were admitted. Patients presented with clinical features emerging from cranial nerve deficits, motor nerve disability, cerebellar dysfunction, and MRI evidence of a large, expansile lesion with irregular margins. The diagnosis of DIPG was clinically made after evaluation by a pediatric oncologist, radiation oncologist, neurosurgeon, and radiologist in the multidisciplinary tumor board. All patients had adequate hematologic, renal, and hepatic functions (hemoglobin level > 11 g/dl, total leukocyte count > 4,000/mm3 with absolute neutrophil count > 1,500/mm3 and platelet count > 100,000/mm3; liver enzyme level < 2.5 upper limit of normal; and serum creatinine level < 1.5 upper limit of normal). Cranial MRI was obtained from all patients at diagnosis and was repeated every 3 months during treatment and after therapy. All patients received RT as the standard treatment. In our institution, RT treatment was given solely without concomitant/adjuvant chemotherapy before the year 2000 (group 1 RT only). RT was administered to the tumor bed plus 2-cm margins with a conventional fractionation of 180–200 cGy once a day for 5 days a week within 6 weeks, with a total dose of 54 Gy. As fractionated daily RT dose was diminished in patients under 3 years of age, four patients were given 60 Gy hyperfractionated RT, a biologically equivalent dose of 54 Gy. The treatment protocol changed after 2000 by the addition of chemotherapy as concomitant/adjuvant treatment after RT. From 2000 to 2004, cis-platinum 40 mg/m2/week or vincristine 1.5 mg/m2/week were used as sensitizers concomitantly during RT, and the combination of CCNU 100 mg /m2 every 4 weeks and vincristine 1.5 mg/m2 every 4 weeks was used after RT (group 3, RT and other chemotherapy). Since 2004, temozolomide (TMZ) (75 mg/m2/day p.o.) for 6 weeks was used concomitantly during RT, followed by TMZ (200 mg/m2/day p.o.) for 5 days with a 28-day cycle after RT as adjuvant chemotherapy for 12 cycles (group 2, RT and TMZ). TMZ was suspended for an absolute neutrophil count lower than 1,500/mm3 and platelet count lower than 100.000/mm3.

Statistical analysis

The median survival was evaluated in the whole group: in group 1, RT only; in group 2, RT and TMZ; and in group 3, RT and other chemotherapy, and the comparison was made between groups 1 vs. 2, group 1 vs. 3, and group 1 vs. any chemotherapy (groups 2 and 3 combined). Overall survival was assessed by the Kaplan–Meier method in all groups, and survival between groups was compared by the logrank test.

Results

The median age of 50 patients (26 female and 24 male) was 7 years (6 months–16 years). They presented with a median period of 30 days (2–630 days) of symptom duration and history. No patient in this series had neurofibromatosis type 1. The most frequent clinical finding was ataxia in 32 (64 %) patients, followed by strabismus in 31 (62 %) patients, and motor weakness in 22 (44 %) patients. The most frequent cranial nerve involvement was the sixth cranial nerve. All patients received RT as the standard treatment. Before the year 2000, 12 patients received RT only (group 1, RT only). From 2000 to 2004, 17 patients received cis-platinum or vincristine as sensitizers during RT, and CCNU + vincristine combination after RT (group 3, RT and other chemotherapy). After the year 2004, 21 patients received TMZ concurrently with RT and after RT (group 2, RT and TMZ). Three of the patients in this group were biopsied, and the results were pilocytic astrocytoma. During TMZ treatment, clinical deterioration was thought to be due to pseudoprogression in three patients, and TMZ was not stopped. The patients recovered after dexamethasone treatment which was gradually stopped. Twelve total cycles were planned in 21 patients. After 8 cycles of TMZ, the dose was diminished to 75 % in ten patients, but the intervals had to be prolonged in the last 2 cycles to a 42-day cycle in three patients due to thrombocytopenia. Forty thrombocyte transfusions were given as the platelet count < 20,000/mm3. No patients required erythrocyte transfusions. There was no hospitalization due to febrile neutropenia. The median survival time among all patients was 13 months (1–160 months) (Table 1). Group 2 patients who received RT and TMZ had a significantly higher overall survival than patients in group 1 who only received RT (p = 0.018). Group 3 patients who received RT and other chemotherapy had a significantly higher survival than patients in group 1 who only received RT (p = 0.013). Patients receiving any chemotherapy (groups 2 and 3 combined) had a significantly higher survival than patients in group 1 who only received RT (p = 0.005) (Fig. 1; Table 1). At 1-year follow-up, there were no survivors in group 1 who only received RT; 13 of 21 patients in group 2 who received RT and TMZ were dead of disease; 13 of 17 patients in group 3 who received RT and other chemotherapy were dead of disease; thus, 26 of 38 patients are failures in groups 2 and 3 combined (Table 1). In group 2, ten patients who received RT and TMZ survived at 2 years, and five patients survived at 3 years; three patients in group 3 who received RT and other chemotherapy also survived at 3 years. Survival at 2 and 3 years was significantly higher in patients receiving any chemotherapy (groups 2 and 3 combined) vs. group 1 who only received RT (Table 2). Ten patients died on the ventilator; eight died in 5 days. Only two patients who received RT and TMZ survived 2 months upon ventilator in group 2.

Table 1 Comparison of median survival and 1-year survival between group 1, group 2, group 3, and group 2 + 3
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Fig. 1
figure 1

a Comparison of overall survival for group 1 RT only (solid line) and group 2 RT and TMZ (dashed line). b Comparison of overall survival for group 1 RT only (dashed line) and group 3 RT and other chemotherapy (solid line). c Comparison of overall survival for group 1 RT only (dashed line) and group 2 + 3 RT and any chemotherapy (solid line)

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Table 2 Survival rates of patient groups at 1, 2, and 3 years
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Discussion

DIPG are currently associated with a very poor prognosis due to their unresectable nature, devastating neurological lesions associated with the local extension, and poor response to adjuvant therapy. The origin of these tumors is glial in more than 90 % of the cases, with 70 % of the tumors arising in patients younger than 7 years of age (median age at diagnosis, 5–9 years) [19, 22]. Similarly, our study group had a median age of 7 years (6 months–16 years) at diagnosis. Manifestations include combinations of cranial nerve palsies and ataxia. Cranial nerves VI and VII are the most commonly affected, although cranial nerves III, IV, IX, and X may be also compromised [19, 22]. We established similar findings in our study as the most frequent clinical findings were ataxia, strabismus, and motor weakness.

RT is the standard treatment for DIPG with external local field RT at a total dose of 54–60 Gy in 6 weeks. Many techniques such as hyperfractionated RT and increasing RT doses to 78 Gy have been tried with no alteration in time to progression [16, 23]. Several chemotherapeutic agents investigated previously offered no significant improvement. Doz et al. [9] and Bernier-Chastagner et al. [3] used radiosensitizers during RT and reported no improvement in survival. Wagner et al. [28], in the HIT-GBM data reported the 1-year overall survival rate as 45.8 % in patients treated with both RT and CT, although no patients in this database survived longer than 3.9 years. Massimino et al. [21] established no survival advantage within four protocols used in their mono-institutional study in 20 years’ time.

After TMZ was reported to be the standard chemotherapy for adults with newly diagnosed glioblastoma, studies of TMZ on children with high-grade gliomas were undertaken. It was also tried in other relapsed brain tumors including DIPG in children [1, 18]. TMZ produces its cytotoxicity by the DNA methylation of the guanine at the O6 position. It may be useful to evaluate the methylguanine DNA methyltransferase (MGMT) promoter methylation status of the tumor tissue. If there is an expression of MGMT recovery enzyme, it may take away the methyl or alkyl group and put the normal guanine in place and thus cause resistance to TMZ [25]. Despite the initial positive responses observed among children with high-grade gliomas treated in phase I trials, Broniscer et al. [4] reported a disappointing response to TMZ in children. Accordingly, Sirachainan et al. [26], Jalali et al. [15], Kim et al. [17], Chassot et al. [5], and Cohen et al. [7] established no improvement in the outcome of DIPG patients with RT–TMZ (Table 3). Small series have recently suggested that the biology of DIPG is fundamentally different from that of supratentorial anaplastic astrocytoma and glioblastoma multiforme [24, 30]. Another point is that epigenetic silencing of the MGMT gene by promoter methylation is suggested to enhance the cytotoxic impact of TMZ [25]. The limitations of those studies are the lack of information about the biologic character or the MGMT promoter methylation status of the tumor tissues of patients like those in our series. It may be that some tumors may be more responsive to MGMT and have a better response to TMZ. In our series, although there was no survivor at 2 and 3 years among only RT receivers, ten patients survived at 2 years and five patients survived at 3 years in group 2 who received RT and TMZ. Three patients in group 3 who received RT and other chemotherapy also survived at 3 years. Thus, we suggest concurrent and/or adjuvant chemotherapy with RT; it might improve survival in some DIPG patients. Moreover, there might be other prognostic factors like more frequent visits for weekly chemotherapy administration and requirement for blood counts in the last decade according to changes in chemotherapy in our series. Thus, the symptoms and positive findings of disease progression could be met earlier, and decision of arranging a shunt or percutaneous endoscopic gastrostomy might have a contribution on survival duration concurrently with the technical improvement of these palliative measures over the study period. In addition to that, the parents are more aware of the behavioral changes of their children, and the governments can enable them more improved social facilities such as home nursing or hospice services in time. Hence, more free time out of bed might possibly enhance the well-being of the children as Temel et al. [27] reported that early palliative care led to significant improvements in both quality of life and mood.

Table 3 Summary of the studies reporting the results of concomitant and adjuvant temozolomide in children with diffuse intrinsic pontine glioma
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Our retrospective study has the limitation of a long duration so that standardization of chemotherapy and RT applications is not possible, but development in RT technicals might also contribute such improved results in time.

In conclusion, TMZ and/or other chemotherapeutic agents might change the poor outcome of children with newly diagnosed DIPG. The limitation of this study is its retrospective design, long duration, and the small sample size. The complex biology of DIPG renders an unselected single-agent approach less likely to be effective. Instead, a multitargeted approach seems to be required to improve the prognosis.