PROTON THERAPY FOR RE-IRRADIATION OF PEDIATRIC DIFFUSE BRAIN STEM TUMORS

re-irradiation is an treatment can sustain and improve the quality of life and prolong survival in children with BS

the very few therapeutic options for progressive or recurrent BS tumors [14][15][16]. Therapy against childhood BS tumors seeks to sustain or improve the quality of life and prolong survival. This goal can be achieved through using state-of-the-art RT, including proton RT [17,18].

Clinical case
Below we report a clinical case of a pediatric patient with a recurrent diffuse BS tumor treated with re-irradiation (proton therapy) at the Federal Research and Clinical Center for Medical Radiology and Oncology (FMBA, Dimitrovgrad, Russia) [19]. Patient G, 9 years, was first diagnosed with unverified diffuse BS glioma (С71.7) in July, 2019. The patient suffered a relapse in December 2020. Stabilization was achieved till September 2021. The patient's condition was complicated by obstructive hydrocephalus.
At the age of 9 (prior to diagnosis), the patient started complaining of headaches, gait disturbance, squinting, and morning vomiting. Brain MRI performed on July 10, 2019 was suggestive of a diffuse BS neoplasm 58 × 34 × 40 mm in size spreading to the right pons, the right peduncle and the hemisphere of the cerebellum (Fig. 1).
From August 2 to September 12, 2019, the patient was undergoing 3D conformal photon RT at the total dose of 54 Gy delivered in 1.8 Gy per fraction (Fig. 2).
Two months after the initial RT course, brain MRI performed on October 31, 2019 showed no contrast enhancement, suggesting tumor regression (Fig. 3). 11 С-methionine PET/CT conducted on November 5, 2019 detected no signs of metabolic tumor activity in the brain structures.
The patient was followed up for 15 months. Then, brain MRI (December 8, 2020) and 11 С-methionine PET/CT (January 11, 2021) were suggestive of diffuse changes in BS and increased radiopharmaceutical uptake in the pons (uptake ratio: 2.2); the lesion size on PET/CT was 21 × 15 × 22 mm, which was consistent with MRI findings (Fig. 4).
Considering the medical history of the patient, time elapsed from the first RT course and the fact of tumor recurrence, proton re-irradiation was recommended by the case conference panel.
Optimized intensity-modulated proton therapy [17] for the metabolically active recurrent lesion was delivered to the patient at the Federal Research and Clinical Center for Medical Radiology and Oncology from January 26, 2021 to March 5, 2021. Dose planning was based on 11 С-methionine PET/CT findings. A ProteusPlus 235 system (IBA; Belgium) was used for irradiation. Therapy was delivered in 28 daily fractions (1.8 Gy or per fraction); the total dose was 50.4 Gy. Glucocorticoids were administered concomitantly to reduce cerebral edema. PTV dose coverage D98% was 98% Gy of the prescription dose (Fig. 5). No adverse effects were observed. By the end of the treatment course, the tumor had regressed completely.
The patient was discharged home. Further follow-up with a local pediatric oncologist and other involved specialists was recommended. As of September 2021 (6 months after reirradiation), there had been no signs of recurrent tumor growth, neurologic deficit or VPS dysfunction.

Discussion
Diffuse intrinsic pontine glioma (DIPG) is the primary cause of pediatric mortality from CNS malignancies. This aggressive tumor makes up 75-80% of pediatric BS malignancies and 10% of all pediatric CNS tumors [20][21][22]. Prognosis for DIPG is much poorer than for other BS tumors and malignant gliomas because the pons contains structures that control vital body functions like breathing, heart rate and arterial pressure [22]. Despite countless clinical trials of chemotherapy drugs and biological response modifiers, children with BS tumors still die, typically within 1 year after diagnosis [16,[20][21][22][23][24]. There is no effective treatment for recurrent/progressive BS tumors after initial RT. The average time to death after tumor recurrence is 3 months [25]. Various approaches, including RT and systemic drug therapy, tried for refractory and recurrent pediatric BS tumors are not standardized. RT is the only treatment option that has been shown to prolong survival in patients with recurrent/progressive DIPG [26,27]. As more evidence is being accumulated about the safety of this approach for treating pediatric CNS tumors, re-irradiation is being increasingly used to manage recurrent/progressive DIPG in children [28][29][30].
RT is an important component of therapy for many pediatric CNS tumors, including DIPG. Re-irradiation is a safe option for managing recurrent ependymomas and medulloblastomas. It prolongs progression-free survival and, although there has been only 1 non-randomized phase 2 trial of this method, it has been shown to be a safe therapy for progressive DIPG [26,29,30]. Currently there are no treatment standards for re-EXTREME MEDICINE 4, 23, 2021 MES.FMBA.PRESS | | In one of such studies, 5 children underwent re-irradiation and concomitant chemotherapy for progressive DIPG at the University of Texas MD Anderson Cancer Center. The following regimens were applied: 18 Gy in 1.8 Gy per fraction for 1 patient and 20 Gy in 2 Gy per fraction for 4 patients. Adverse events were minimal (≤ grade 2 RTOG). The median time to progression was 5 months [31].
An Italian research team studied the effects of radiation and concomitant therapy with nimotuzumab and vinorelbine in a phase 2 trial which included first-time patients with DIPG; relapsing patients were treated with re-irradiation. Tumor progression occurred in 20 patients; of them, 16 had a local recurrence. Focal re-irradiation of the locally progressing lesion (total dose of 19.8 Gy delivered in 1.8 Gy per fraction) was performed on 11 patients. Four of 5 other relapsing patients with metastatic tumor spread received focal re-irradiation for the primary lesion and its metastases. This approach was well tolerated, no unexpected adverse events or neurological status deterioration were observed. Survival after re-irradiation ranged from 6 weeks to 14 months and was 6 months on average [32].
Another European research team conducted a retrospective analysis of DIPG cases, including 31 patients who had received re-irradiation for the first tumor progression (total dose: 30 Gy delivered in 1.8 Gy per fraction); in addition to RT, some patients had received chemotherapy. Clinical improvement was observed in 77% patients, no life-threatening radiation toxicity was reported after re-irradiation. However, the study underscores that a combination of repeat RT and chemotherapy can produce lethal toxicity. Average survival in the study was 6.4 months after re-irradiation vs 3 months in the historical control group (no re-irradiation therapy) [15].
In another retrospective review published by Canadian researchers, re-irradiation was used on 16 patients with progressive DIPG. Focal re-irradiation therapy was delivered to 14 patients (total dose: 21.6-36 Gy). Two patients had to undergo whole-brain radiotherapy (total dose: 30.6 Gy) due to of metastasis. The applied RT doses varied, the total dose ranged from 12 to 36 Gy and was 24 Gy on average. The average re-irradiation dose per fraction was 2 Gy (1-9 Gy). The average time to progression after diagnosis was 10.5 months (4-37 months). One patient relapsed 6 months after re-irradiation and had to undergo one more course of reirradiation therapy (total dose: 21.6 Gy). One patient received concomitant therapy with bevacizumab. The rest were treated with RT only. Following the course of re-irradiation, 7 patients were prescribed chemotherapy with temozolomide, valproic acid, nimotuzumab, or bevacizumab. Re-irradiation was mostly well tolerated except for one patient who developed necrosis of the pons which caused cerebellar dysfunction and tetraparesis after exposure to the total dose of 30 Gy delivered in 3 Gy per fraction. Six patients did not require steroids; 4 patients discontinued steroids at the end of the re-irradiation course.  [16]. Russian researchers have retrospectively analyzed the outcomes of re-irradiation among 20 children with different BS tumors undergoing treatment between 2001 and 2011. All of the children received re-irradiation after the initial RT (total dose: 50-55 Gy) course (combined with temozolomide in 7 cases). Re-irradiation was prescribed for clinically and radiographically confirmed tumor progression. Time between the end of the initial treatment and the beginning of re-irradiation therapy ranged from 5 to 32 months and was 12 months on average. Reirradiation was delivered in combination with adjuvant systemic chemotherapy: temozolomide (10 patients) and bevacizumab (3 patients). The total re-irradiation dose was < 30 Gy for 10 patients, 31-45 Gy for 9 patients and 50 Gy for 1 patient. While in treatment, 5 patients with radiographic signs of tumor destruction deteriorated and their therapy was terminated. The average survival time for those patients was 3.5 months. Other patients did not have signs of tumor destruction on MRI and their condition was improving. They were able to achieve complete or partial regression of neurological symptoms. In this subgroup, 93% survived 6 months after re-irradiation, 53% survived 1 year, 40% survived 1.5 years, and 20% survived 2 years. One patient stayed alive for 5 years after re-irradiation and died at the age of 13. Another patient developed symmetric necrotic lesions in the cerebellar hemispheres in the setting of persistent tumor growth detected on MRI 5 months after reirradiation (total dose: 50 Gy) [2,3,8,14].
Literature analysis and clinical experience show that pediatric diffuse BS tumors are currently incurable. The best effect that a combination of RT and chemotherapy can achieve is stabilization of tumor growth. Although there are no treatment standards regulating the use of re-irradiation therapy for pediatric CNS tumors, re-irradiation is an effective option that can sustain or improve the quality of life and prolong survival in children with diffuse BS tumors [34].

CONCLUSION
Modern RT, including proton re-irradiation, is an important component of combination therapy for diffuse BS tumor, especially in pediatric patients with complicated medical history.