https://orcid.org/0000-0002-2861-2573
Figures
Abstract
Background
With the introduction of new therapy modalities and the resulting increase in survival rates, childhood brain cancers have become a focal point of research in pediatric oncology. In current protocols, besides surgical resection and chemotherapy, radiotherapy is required to ensure optimal survival. Our aim was to determine which of the two major irradiation options, proton (PT) or photon (XRT), was the least harmful yet effective for children with brain tumors.
Methods
The protocol was registered on PROSPERO in advance (CRD42022374443). A systematic search was performed in four databases (MEDLINE via (PubMed), Embase, Cochrane Library, and Scopus) on 23 April 2024. Odd ratios (OR) and mean differences (MD) with 95% confidence intervals (CI) were calculated using a random-effects model. Survival and six major types of side effects were assessed based on data in the articles and reported using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Heterogeneity was assessed using Higgins and Thompson’s I2 statistics.
Results
Altogether, 5848 articles were screened, of which 33 were eligible for data extraction. The 5-year overall survival results showed statistically no significant difference between the two radiotherapy modalities (OR = 0.80, 95% CI: 0.51–1.23, p = 0.22, I2 = 0%). In terms of toxicity rates, an advantage was found for PT, particularly in terms of chronic endocrine side effects (hypothyroidism OR: 0.22, 95% CI: 0.10–0428, p = 0.002, I2 = 68%), neurocognitive decline (global IQ level MD: 13.06, 95% CI: 4.97–21.15, p = 0.009, I2 = 68%). As for hematological, acute side effects, neurological changes and ophthalmologic disorders PT can be beneficial for survivors in terms of reducing them.
Conclusions
In comparison with XRT, PT can reduce most side effects, without significantly decreasing the survival rate. There is considerable clinical relevance in the findings, even not all of them are statistically significant, which may facilitate the development of protocols regarding the usage of radiotherapy methods, and may encourage the establishment of more proton centers, where more studies can be done.
Citation: Kiss-Miki R, Obeidat M, Máté V, Teutsch B, Agócs G, Kiss-Dala S, et al. (2025) Proton or photon? Comparison of survival and toxicity of two radiotherapy modalities among pediatric brain cancer patients: A systematic review and meta-analysis. PLoS ONE 20(2): e0318194. https://doi.org/10.1371/journal.pone.0318194
Editor: Nobuyuki Hamada, Central Research Institute of Electric Power Industry (CRIEPI), JAPAN
Received: May 30, 2024; Accepted: January 11, 2025; Published: February 20, 2025
Copyright: © 2025 Kiss-Miki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Tumors of the brain or central nervous system (CNS) represent a major challenge in pediatric oncology, with a high impact on the quality of life of these young patients. More than 4,000 CNS tumors are diagnosed in children every year [1]. With this number, this pathology represents a huge challenge for pediatric neuro-oncologists, but it is a burden for the family and the society as well.
In the last decades, there has been a huge development in the field of treatment, both in chemotherapy agents and in the radiotherapy part as well. Although effective in managing tumor growth [2,3], traditional radiation treatment methods are often associated with a number of side effects that can detrimentally affect the development and overall well-being of a child [3]. The need for a more targeted and less harmful treatment approach is imperative. Proton radiotherapy, with its unique dose characteristics, has recently emerged as a promising solution to this problem [4–6].
Causes of childhood brain cancers vary, and besides genetic factors, numerous epigenetic factors could be identified, such as low birth weight [5,7], parental lead exposure [8], non-chromosomal structural birth defects, or higher socioeconomic position [9].
Besides chemotherapy and surgery, radiotherapy plays an important role in treatment protocols. Two major radiotherapy modalities can be identified: the oldest is photon therapy (XRT), which has undergone significant development in the last decades. Intensity-modulated therapy (IMRT), stereotactic radiosurgery, and stereotactic body radiation therapy (SBRT) are promising techniques [10,11]. The newest radiotherapy method (IMRT) was developed with many promising outcomes by reducing the toxicity, but may also lead to adverse events by triggering different biological processes [12].
On the other hand, proton therapy (PT) represents a new and significant advancement in the treatment of pediatric brain tumors. Despite the fact that the radiobiological effect is similar between proton and photon therapy, there is a robust difference considering healthy tissue sparing [13]. As technology continues to advance and more clinical research is conducted, PT is expected to become an even more integral part of pediatric oncology.
Children receiving radiotherapy are at risk of neurocognitive decline, neuroendocrine dysfunction, hearing loss, vascular anomalies, psychosocial dysfunction [2,14,15], secondary cancer development [2,16], and acute toxicities (e.g., nausea, vomiting, fatigue) [2,17]. The risk of these side effects correlates with the area irradiated [16].
Currently, there is no complex and comprehensive consensus (evidence-based) in the literature regarding the therapeutic recommendations for XRT and PT in childhood brain tumors. This study aims to compare the efficacy and safety of XRT with PT in the treatment of pediatric brain cancer patients, drawing on a systematic review and meta-analysis of existing literature.
Our hypothesis was that PT modalities would be more effective and less harmful for pediatric brain cancer patients compared to XRT.
Methods
We report our systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [18] (S1 Table in S1 File); the recommendations of the Cochrane Handbook were also followed [19]. The protocol was registered on PROSPERO (CRD42022374443) in advance, and we fully adhered to it; however, some changes were necessary because of the statistical analysis of data in the articles.
Ethical approval
No ethical approval was required for this systematic review with meta-analysis, as all data were already published in peer-reviewed journals. No patients were involved in the design, conduct, or interpretation of our study.
The datasets used in this study can be found in the full-text articles included in the systematic review and meta-analysis.
Eligibility criteria
We included studies of children with brain tumors who received XRT or PT and reported side effects based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 or data on overall survival (numerical data or Kaplan Meier curves). All comparative study types and abstracts were also included in the analysis, in which both XRT and PT were investigated by the same working group and enough amount of information was provided regarding the two modalities and outcomes. Articles investigating only one radiotherapy modality or describing dose comparison or therapy modeling were ultimately excluded, such as articles from where data were missing regarding the measured outcomes, or they were reported in a non-reproducible way.
We used the PICO framework (population, intervention, comparison, outcome) [20] to define our eligibility criteria. We investigated PT as an intervention versus XRT as a comparator in the population of children with brain tumors with our outcomes, including survival, neurocognitive decline, hematological, endocrine, neurological, ophthalmologic, acute and other side effects.
Information sources
Our systematic search was conducted on 25 November 2022 and updated on 23 April 2024 in four databases: MEDLINE via PubMed (n = 1400), Embase (n = 1890), Cochrane Library (n = 9), and Scopus (n = 653 with title abstract selection). No restrictions were applied. Additionally, backward and forward citation searching was conducted after completion of the full-text selection to identify other potentially relevant publications.
Search strategy
Our search key consists of four main domains: pediatric population, brain cancer, photon, and proton radiotherapies. For the detailed search strategy, see S2 Table in S1 File.
Screening and selection
After the systematic search, we imported the articles into the reference management system (EndNote 20.1). Duplicate articles were eliminated automatically and manually based on overlapping years, authors, and titles. Screening and selection were done by two independent reviewers (R.K-M and J.K), first by title-abstract selection and then by full-text selection. Cohen’s kappa was calculated at all levels of selection. In case of disagreement, consensus was reached after discussion with the corresponding author (M.G). No automation tools were used in the selection process.
Data extraction
Data from the eligible articles were collected independently by two authors (R.K-M and J.K). Disagreements were resolved by involving the corresponding author (M.G). All data were collected manually and entered an Excel spreadsheet (Office 365, Microsoft, Redmond, WA, USA) for analysis. During data extraction, we identified conference abstracts and articles with the same population, one of which had the largest sample size or the most reported side event outcomes.
Data items
The following data were extracted: first author, year of publication, study population, study period and patient data and demographics (e.g., number of patients included, tumor type, age), dose of radiotherapy, follow-up period and outcomes investigated: endocrine deficit (hypothyroidism, growth hormone, sex hormone and adrenal deficiency), ototoxicity, neurocognitive decline outcomes (intelligence quotient (IQ), verbal reasoning, perceptual reasoning, working memory, processing speed), hematological outcomes (anemia, leukopenia, lymphopenia, thrombocytopenia, neutropenia), acute side effects (nausea, vomiting, ophthalmic disorder, neurological disorder, skin disorders, fatigue, headache, diarrhea, constipation, anorexia, insomnia, esophagitis, abdominal pain) and others (body mass index, obesity, vascular injury, ventriculo-peritoneal shunt placement).
Outcomes were reported in most of the articles using the CTC-AE scale. For hematological outcomes, we used grade 3 and 4 toxicity.
Neurocognitive domains in the articles [21–25] were measured using different age adapted questionnaires, such as the Wechsler Intelligence Scale IV and V, the Woodcock-Johnson Test of Cognitive Abilities, and the Stanford-Binet Intelligence Test.
Overall survival was analyzed using raw data reported in the articles and the Kaplan-Meier curves using a plot analyzer (software or website).
Risk of bias assessment and quality of evidence
Two authors (R.K-M, J.K) independently assessed the risk of bias using the Risk of Bias in Non-randomised Studies-Intervention (ROBINS-I tool) [26]. To assess the quality of evidence of our results. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) [27] approach and used the GRADEpro tool (software). Study design, risk of bias, inconsistency, indirectness, and imprecision were the determinant factors.
Synthesis methods
Statistical analysis was conducted using the statistical software R (version 4.1.2.) [28] and the meta package (version: 6.1.0) was used [29]. A minimum of three studies were required to perform statistical analysis. We used forest plots to summarize the findings of the studies and present the pooled result.
For dichotomous outcomes, pooled odds ratios (OR) were calculated with 95% confidence intervals (CI) using the Mantel-Haenszel method of random-effects [30]. Tau squared was estimated with the Paule-Mandel method [31].
For continuous outcomes, pooled mean differences (MD) were calculated with 95% CI using random-effects models and the inverse variance method. Tau squared was estimated using the restricted maximum-likelihood method [32].
In all cases, heterogeneity was examined by calculating the Higgins & Thompson I squared statistics [33] indicator and performing the Cochrane Q test [32]. Hartung-Knapp adjustments were also applied where necessary.
We performed a sensitivity analysis, including a leave-one-out influential analysis, to observe whether omitting one study was going to result in a considerable change in our results.
Results
Search and selection
Altogether, 5848 studies were identified using our search key in the four databases. After duplicate removal, we screened 2639 articles by title and abstract, and 73 articles were selected by full text, of which 54 were eligible for full text selection. Ten conference abstracts were excluded due to data being comprehensively reported elsewhere. In the end, 33 papers were eligible for data extraction. The selection process is presented in the PRISMA flowchart (Fig 1).
Basic characteristics of studies included
Altogether, data from 2900 patients (1423 in the photon group and 1477 in the proton group) were collected from the articles and analyzed. The studies were conducted in the USA (mainly Texas), Spain, Germany, Denmark, United Kingdom and Korea. Baseline characteristics of the enrolled articles are presented in Table 1. Nine of the 33 studies were conference abstracts [34–41].
Overall survival
We found data on overall survival (three, five, ten years) in seven articles [38,43,46,51,53,56,58], in six of which Kaplan-Meier survival curves were also detected and analyzed. Survival data were available for five of the seven five-year, two of the articles for three years and one for 10 years. There was no statistically significant difference between the XRT and PT group for 5-year overall survival (OR: 0.80, 95% CI: 0.51–1.23, I2 = 0%, p = 0.224) (Fig 2). Data from the Kaplan-Meier curves for 3, 6, and 9-year survival can be found in the Supplementary Material, where survival probabilities were calculated, with no difference between the two radiotherapy modalities statistically (S1, S2, S3 Figs in S1 File).
OR: odds ratio, CI: confidence interval. Events means survival.
Endocrine side effects
We analyzed the most frequent ones: hypothyroidism [21,36,39,44,45,47,50–52,60,63], growth hormone deficiency [39,47,51,60,63], and sex hormone deficiency [47,50,51,63]. A total of 937 patients were analyzed for hypothyroidism. In this cohort, the odds of developing hypothyroidism were almost five times higher with XRT than with PT(OR: 0.22; 95% CI: 0.10–0.48; I2 = 68%, p = 0.002) (Fig 3).
OR: odds ratio (proton/photon), CI: confidence interval.
For growth hormone deficiency (OR: 0.69, 95% CI: 0.16–2.89, I2: 85%, p = 0.508) and sex hormone deficiency (OR: 0.39, 95% CI:0.09–1.63, I2 = 47%, p = 0.127), the number of patients was substantially lower, and the differences were not statistically significant (S4 and S5 Figs in S1 File).
Neurocognitive side effects
Neurocognitive domains in the articles [21–25,61,62] were measured using different questionnaires, with mean scores as measures of effect. In terms of IQ level changes (MD: 13.06; 95% CI: 4.97–21.15; I2: 68%, p: 0.009), higher IQ scores were observed when patients received PT (Fig 4). Patients receiving PT performed better in terms of working memory (MD: 6.99, 95% CI: −4.10 - 18.08, I2: 74%, p: 0.155), processing speed (MD: 7.58, 95% CI: 0.37–14.78, I2: 68%, p:0.042), and perceptual reasoning (MD: 10.51 95% CI: −0.43 to 21.45, I2: 57%, p: 0.055) compared to patients receiving XRT (S6, S7, and S8 Figs in S1 File).
MD: mean difference, CI: confidence interval.
Acute side effects and others
Among the acute side effects, only nausea, vomiting, and skin disorders were reported in at least three articles. The reported side effects were grade 3 or higher. Reduction in nausea was observed [35,37,49,54] in patients receiving PT (OR: 0.30, 95% CI: 0.11–0.78, I2: 0%, p: 0.028) versus XRT; however, there no statistically significant difference was observed for vomiting [49,54,55](OR: 0.37, 95% CI: 0.03–4.97, I2: 37%, p: 0.243) (Fig 5).
OR: odds ratio (proton/photon), CI: confidence interval.
Based on skin disorder there was statistical no difference between the radiotherapy methods (OR: 0.69, 95% CI: 0.13–3.80, I2:0%, p: 0.453) [59].
Data about the ototoxicity was found in three articles, and based on the statistical analysis there was no difference between the radiotherapy methods (OR:0.78, 95% CI: 0.40–1.52, I2: 0%, p: 0.249) [23,42,59]. (S9 Fig in S1 File).
The appearance of neurological side effects (OR: 0.78, 95% CI: 0.09–6.90, I2:43%, p: 0.744) [49,56,58,59] and ophthalmologic disorders (OR: 0,96, 95% CI: 0.05–17.45, I2: 57%, p: 0.971) [46,49,58,59] was not significantly different between the two radiotherapy modalities (S10, S11 Figs in S1 File).
Hematological side effects
For hematological adverse events, grade 3 and 4 side effects were analyzed. In the majority of articles concomitant chemotherapy was administered based on personal protocol. For grade 3 anemia, five articles were included in the analysis [35,38,49,54,55], (OR: 0.37, 95% CI: 0.05–2.95, I2: 69%, p: 0.252) (Fig 6). Interestingly, grade 3 leukopenia (OR: 1.24, 95% CI: 0.31–4.86, I2: 52%, p: 0.657) was observed less frequently in XRT as opposed to grade 4 leukopenia (OR:0.35, 95% CI: 0.06–1.96, I2: 0%, p: 0121). When grade 3 thrombocytopenia was considered (OR: 0.55, 95% CI: 0.50–0.61, I2: 0%, p: 0.002), there was a statistically significant difference in favor of PT. For thrombocytopenia grade 4 (OR: 0.61, 95% CI: 0.03–11.84, I2: 35%, p: 0.549), the tendency was that PT could be the better choice, without statistically significant difference. (S12, S13, S14, S15, and S16 Figs in S1 File).
OR: odds ratio (proton/photon), CI: confidence interval.
Risk of bias assessment and quality of evidence
Based on the overall risk of bias assessment, nine articles [21,24,35,43,44,47,61–63] were identified as severe, 14 as moderate [22,23,25,38,42,45,46,49–51,54,57,59,60], and 10 as low risk of bias [35,36,39,41,48,51,52,55,56,58]. The results of the risk of bias assessment are presented in S3 Table in S1 File.
In terms of quality of evidence, all our results had moderate or serious risk of bias. A summary of the findings table can be found in the Supplementary Material (S4 Table in S1 File).
Publication bias and heterogeneity
We included less than 10 articles per outcome, which is why Egger’s test was not performed. Generally, we have a homogeneous population. In most of the analyses, moderate heterogeneity was observed. This can be due to different study populations, follow-up times, or follow-up protocols used.
Discussion
This is the first meta-analysis to compare the efficacy and side-effect profile of PT and XRT in children with various types of brain tumors. Only direct comparative studies were included.
Our study found no significant difference between XRT and PT in terms of 5-year overall survival, but there was a significant difference in terms of the incidence of side effects. More children survive cancer treatment each year; thus, to improve their quality of life, the focus should be on minimizing the side effects. A Swedish study found that PT had high potential importance, and it was estimated that 80–100 children could benefit from the therapy each year [64]. In a recent study, where adult medulloblastoma patients were compared based on the used radiotherapy method, found that there is a dosimetric improvement, leading to decreased acute side effects [65].
In this study, the population analyzed received radiotherapy as part of a predefined treatment protocol, and those who received radiotherapy for secondary malignancies were excluded. In a previous meta-analysis, the incidence of secondary malignancies was similar in the two radiotherapy modalities [66] but studies by Xiang and Ludmir et al. found that the incidence of secondary malignancies was lower in PT [11,67]. In another study, there was no difference in the incidence of secondary malignancies between the two radiotherapy modalities [68]. There was also no difference in the incidence of radiation-induced cavernomas between the two radiotherapy modalities [69].
The indications for PT and XRT may be different based on the tumor type. In the studies included, no differences were identified by tumor type or age, all results were published based on overall findings [70].
The 5-year overall survival from the articles and 3,6,9-year data from curves showed that both radiotherapy modalities were safe, demonstrating favorable outcomes. Since PT reduces late adverse events, PT can potentially lead to a better survival outcome over a longer period than XRT, PT can deliver the desired target dose more precisely to the target area, however, the results show the contrary regarding overall survival rate. While the overall survival results show that both are safe with time, with more studies the result can be reversed.
We analyzed the most frequent endocrine side effects. In hypothyroidism, growth hormone, and sex hormone deficiency, we observed a clear effect on the plots. We obtained data from two articles on adrenal insufficiency [45,51] and precocious puberty [51], stating that PT was beneficial in reducing this endocrine side effects as well.
Different, age adapted scales were used to assess the level of decline in the neurocognitive changes group. All articles included mentioned that these scales correlated with each other and could be pooled together, that is why mean difference was used as measure of effect. We are aware that the neurocognitive decline can be affected by radiation dose and target area as well, but there is no clear distinction regarding radiation dose variations. All the domains measured showed that PT was more likely to result in higher neurocognitive performance on these scales compared to XRT. A previous meta-analysis, where neurocognitive outcomes were measured from the same articles as in our study, also concluded that patients who received PT scored higher on neurocognitive outcomes [48]. In three systematic reviews, the main conclusions were the same as in our case: there is a need to use and establish proton centers to reduce neurocognitive side effects [55,71,72].
We collected data on the incidence of acute side effects such as nausea, vomiting, dysphagia, anorexia, diarrhea, constipation, fatigue, headache, insomnia, esophagitis, abdominal pain, neurological disorders, ophthalmologic, and skin disorders. Data on nausea, vomiting, neurological side effects, and ophthalmologic disorders were pooled together because of the lack of data in the articles. Our results showed that PT could reduce the incidence of acute side effects. Results regarding ophthalmologic side effects are similar to a study from 2022, where radiotherapy was compared in the case of optic pathway gliomas [73]. Neurological side effects included ataxia, cranial nerve disturbance, weakness, seizures, dysarthria, somnolence, balance disturbance, and speech problems. Measurement of the effects showed that there was no difference between the two radiotherapy modalities, but there was a tendency for PT to have a beneficial effect in reducing these side effects.
Hematological side effects are more common after chemotherapy; however, radiotherapy can also facilitate their development. These side effects were graded according to the CTC-AE scale, version 4 or 5. Clinically, the most important grades are grades 3 and 4. By the investigation of grade 4 anemia, three articles [38,49,54] provided data. Two of them [38,49] described 0 events; however, in the third [54], half of the patients developed grade 4 anemia in the proton cohort and 1/3 in the photon cohort, which could be due to the different checkup protocols. No other causes could be identified during data collection. In this analysis, PT were more useful as a protective therapy, considering hematological toxicity.
Ototoxicity is a very common side effect in the case of radiotherapy; however, a few studies were identified with appropriate data reporting for this outcome. A retrospective study [42] showed that the use of PT resulted in low early high-grade ototoxicity, as in our results.
Event-free survival was not available in the articles, only progression-free, recurrence-free, and disease-free survival, but none was available in at least three articles.
Based on our study, the overall well-being of survivors can be increased by using PT. In addition, a previously published systematic review, where articles with non-CNS tumors were also included, showed the same findings, as in case of studies including pediatric and adult medulloblastoma patients as well [65,70,72]. With a running multicenter cohort study, where the authors would like to highlight the difference of second cancer risk as well, the French radiotherapy guide and our study, it can be changed the management of radiotherapy among pediatric brain cancer patients, and also a protocol can be designed for a better treatment plan with a high quality of life after treatment [74,75].
Even though some of our results were statistically not significant, there is considerable clinical relevance in the findings which may facilitate the development of protocols regarding the usage of radiotherapy methods, and may encourage the establishment of more proton centers, where more studies can be done.
Strengths and limitations
Regarding the strengths of our analysis, we followed our protocol, which was registered in advance. A rigorous methodology was subsequently applied. In addition, this is the first comprehensive meta-analysis where multiple outcomes were assessed.
Considering the limitations of this study, we included a small number of articles in our study. The follow-up period was different in the articles, and different types of tumors were analyzed, most of which were medulloblastomas. The presence of moderate and high risks of bias in some of the domains is another limitation. In the case of neurocognitive decline, test results before the radiotherapy were not reported, only those from the last checkup; therefore, the change from baseline could not be assessed. Another limitation is the geographical distribution of the reported studies.
Implication for practice and research
Based on our results, we suggest conducting more two-arm comparative high-quality prospective studies with longer follow-up periods to detect late side effects. This approach will help determine the best treatment strategy. For neurocognitive decline, reporting initial test results can enhance the study quality by allowing proper assessment of changes from baseline. Translational science is vital for closing the gap between clinical research and its application in everyday medical practice [76,77], This systematic and comprehensive assessment contributes to this effort by analyzing data on proton and photon therapies in pediatric brain cancer patients.
Conclusion
PT can be beneficial in reducing postradiotherapy toxicity for children with brain tumors without significantly decreasing survival rate. For this, the implementation of more proton centers and an exchange in the protocol is needed. With this radiotherapy method the life of children after radiotherapy can be improved, and by implementing more centers higher quality studies, with more participants can be conducted in this field, so we could better investigate the efficacy of this promising radiotherapy method.
Key results
1.All the included retrospective cohort studies show us that there is statistically no difference regarding survival (OR: 0.80, 95% CI: 0.51–1.23) in proton or photon-treated patient groups.
2.The frequency of side effects is lower in proton radiotherapy groups as in photon ones, especially in case of hypothyroidism (OR: 0.17, 95% CI: 0.11–0.28), thrombocytopenia grade 3 (OR: 0.55, 95% CI: 0.50–0.61) and nausea (OR: 0.30, 95% CI: 0.11–0.78).
3.Neurocognitive domains, for example IQ level, can be increased by using proton radiotherapy at children with brain cancers (MD: 11.91, 95% CI: 1.91–21.90).
Supporting information
S2 Flie. PRISMA_2020_Flow_Diagram_31-JAN-2025.
https://doi.org/10.1371/journal.pone.0318194.s002
(DOCX)
S3 File. List_of_studies_identified_31-JAN-2025.
https://doi.org/10.1371/journal.pone.0318194.s003
(XLSX)
S4 File. Data_table_with_all_identified_articles_31-JAN-2025.
https://doi.org/10.1371/journal.pone.0318194.s004
(XLSX)
References
- 1.
Official webpage of American Cancer Society.
- 2. Padovani L, Horan G, Ajithkumar T. Radiotherapy advances in paediatric medulloblastoma treatment. Clin Oncol (R Coll Radiol). 2019;31(3):171–81. pmid:30655168
- 3. Bindra RS, Wolden SL. Advances in radiation therapy in pediatric neuro-oncology. J Child Neurol. 2016;31(4):506–16. pmid:26271789
- 4. Mohan R, Grosshans D. Proton therapy - present and future. Adv Drug Deliv Rev. 2017;109:26–44. pmid:27919760
- 5. Dahlhaus A, Prengel P, Spector L, Pieper D. Birth weight and subsequent risk of childhood primary brain tumors: an updated meta-analysis. Pediatr Blood Cancer. 2017;64(5): pmid:27804208
- 6. Merchant TE, Schreiber JE, Wu S, Lukose R, Xiong X, Gajjar A. Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma. Int J Radiat Oncol Biol Phys. 2014;90:554–61.
- 7. Georgakis MK, Kalogirou EI, Liaskas A, Karalexi MA, Papathoma P, Ladopoulou K, et al; NARECHEM-BT Working Group. Anthropometrics at birth and risk of a primary central nervous system tumour: a systematic review and meta-analysis. Eur J Cancer. 2017;75:117–31. pmid:28219020
- 8. Meng Y, Tang C, Yu J, Meng S, Zhang W. Exposure to lead increases the risk of meningioma and brain cancer: a meta-analysis. J Trace Elem Med Biol. 2020;60:126474. pmid:32146339
- 9. Ostrom QT, Francis SS, Barnholtz-Sloan JS. Epidemiology of brain and other CNS tumors. Curr Neurol Neurosci Rep. 2021;21(12):68. pmid:34817716
- 10. Bagheri H, Soleimani A, Gharehaghaji N, Mesbahi A, Manouchehri F, Shekarchi B, et al. An overview on small-field dosimetry in photon beam radiotherapy: developments and challenges. J Cancer Res Ther. 2017;13(2):175–85. pmid:28643730
- 11. Ludmir E, Grosshans D, Woodhouse K. Radiotherapy advances in pediatric neuro-oncology. Bioengineering. 2018;5:97.
- 12. Vanderwaeren L, Dok R, Verstrepen K, Nuyts S. Clinical progress in proton radiotherapy: biological unknowns. Cancers (Basel). 2021;13(4):604. pmid:33546432
- 13. Jumaniyazova E, Smyk D, Vishnyakova P, Fatkhudinov T, Gordon K. Photon- and proton-mediated biological effects: what has been learned? Life. 2022;13(1):30. pmid:36675979
- 14. Christopherson KM, Rotondo RL, Bradley JA, Pincus DW, Wynn TT, Fort JA, et al. Late toxicity following craniospinal radiation for early-stage medulloblastoma. Acta Oncol. 2014;53(4):471–80. pmid:24564687
- 15. Liu KX, Haas-Kogan DA, Elhalawani H. Radiotherapy for primary pediatric central nervous system malignancies: current treatment paradigms and future directions. Pediatr Neurosurg. 2023;58(5):356–66. pmid:37703864
- 16. DeNunzio NJ, Yock TI. Modern radiotherapy for pediatric brain tumors. Cancers (Basel). 2020;12(6):1533. pmid:32545204
- 17. Suneja G, Poorvu PD, Hill-Kayser C, Lustig RA. Acute toxicity of proton beam radiation for pediatric central nervous system malignancies. Pediatr Blood Cancer. 2013;60(9):1431–6. pmid:23610011
- 18. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. pmid:33782057
- 19.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions. 1st ed. Wiley; 2019. https://doi.org/10.1002/9781119536604
- 20. Munn Z, Stern C, Aromataris E, Lockwood C, Jordan Z. What kind of systematic review should I conduct? A proposed typology and guidance for systematic reviewers in the medical and health sciences. BMC Med Res Methodol. 2018;18(1):5. pmid:29316881
- 21. Eaton BR, Fong GW, Ingerski LM, Pulsifer MB, Goyal S, Zhang C, et al. Intellectual functioning among case‐matched cohorts of children treated with proton or photon radiation for standard‐risk medulloblastoma. Cancer. 2021;127(20):3840–6. pmid:34255345
- 22. Kahalley LS, Peterson R, Ris MD, Janzen L, Okcu MF, Grosshans DR, et al. Superior Intellectual Outcomes After Proton Radiotherapy Compared With Photon Radiotherapy for Pediatric Medulloblastoma. JCO. 2020;38:454–61.
- 23. Gross JP, Powell S, Zelko F, Hartsell W, Goldman S, Fangusaro J, et al. Improved neuropsychological outcomes following proton therapy relative to X-ray therapy for pediatric brain tumor patients. Neuro-Oncology. 2019;21(7):934–43. pmid:30997512
- 24. Child AE, Warren EA, Grosshans DR, Paulino AC, Okcu MF, Ris MD, et al. Long‐term cognitive and academic outcomes among pediatric brain tumor survivors treated with proton versus photon radiotherapy. Pediat Blood Cancer. 2021;68(9):e29125. pmid:34114294
- 25. Warren EAH, Raghubar KP, Cirino PT, Child AE, Lupo PJ, Grosshans DR, et al. Cognitive predictors of social adjustment in pediatric brain tumor survivors treated with photon versus proton radiation therapy. Pediat Blood Cancer. 2022;69(6):e29645. pmid:35285129
- 26. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. pmid:27733354
- 27. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. pmid:21195583
- 28.
R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing. 2022. https://www.R-project.org/
- 29.
Schwarzer G. Meta: General Package for Meta-Analysis. 2022.
- 30. Statistical aspects of the analysis of data from retrospective studies of disease. J Nat Cancer Instit. 1959 [cited 6 Jun 2023].
- 31. Paule RC, Mandel J. Consensus values and weighting factors. J Res Natl Bur Stand (1977). 1982;87(5):377–85. pmid:34566088
- 32.
Harrer M, Cuijpers P, Furukawa TA, Ebert DD. Doing Meta-Analysis with R: A Hands-On Guide. 1st ed. Boca Raton: Chapman and Hall/CRC; 2021. https://doi.org/10.1201/9781003107347
- 33. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58. pmid:12111919
- 34. Eaton BR, Esiashvili N, Kim S, et al Clinical outcomes among children with standard risk medulloblastoma in proton and photon treated cohorts. 90(1):S113.
- 35.
Hopper AB, Chou B, Elster J, Guram K, Crawford J, Murphy KT, Chang AL, MacEwan I. A comparison of acute toxicities between vertebral-body- sparing proton craniospinal irradiation and standard photon CSI in pediatric patients.
- 36.
Mehmet O, Danielle A, Vince H, Rona S, Arnold P, Anita M, Kevin B, Murali C, Austin B. Decreased risk of hypothyroidism after proton craniospinal irradiation in medulloblastoma patients. Wiley;
- 37. Lassaletta A, Morales JS, Valenzuela PL, Esteso B, Kahalley LS, Mabbott DJ, et al. Neurocognitive outcomes in pediatric brain tumors after treatment with proton versus photon radiation: a systematic review and meta-analysis. World J Pediatr. 2023;19(8):727–40.
- 38. Liu KX, Ioakeim-Ioannidou M, Susko MS, Rao AD, Yeap BY, Snijders AM, et al. A multi-institutional comparative analysis of proton and photon therapy-induced hematologic toxicity in patients with medulloblastoma. Int J Radiat Oncol Biol Phys. 2021;109(3):726–35. pmid:33243479.
- 39.
Vatner R, Shin S, Legault G, Rosman M, Weyman E, Chan S, et al. Comparison of endocrine dysfunction and dosimetry in pediatric patients treated with proton versus photon radiation therapy for medulloblastoma.
- 40.
Carsten F, Svenja B, Panjarat S, Maria E, Brigitte B, Beate T, et al. Treatment of childhood-onset Craniopharyngioma patients using proton beam therapy versus photon-based radiation therapy in the prospective Kraniopharyngeom 2007 trial.
- 41.
Sara M, Subha M, Rene M-K, Sunnye M, Jim S, Michael A. Comparing the neurocognitive function among patients with pediatric brain tumors treated with proton versus photon radiation therapy.
- 42. Paulino AC, Mahajan A, Ye R, Grosshans DR, Fatih Okcu M, Su J, et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol. 2018;128(1):128–32. pmid:29373195
- 43. Paulino AC, Ludmir EB, Grosshans DR, Su JM, McGovern SL, Okcu MF, et al. Overall survival and secondary malignant neoplasms in children receiving passively scattered proton or photon craniospinal irradiation for medulloblastoma. Cancer. 2021;127(20):3865–71. pmid:34254296
- 44. Bielamowicz K, Okcu MF, Sonabend R, Paulino AC, Hilsenbeck SG, Dreyer Z, et al. Hypothyroidism after craniospinal irradiation with proton or photon therapy in patients with medulloblastoma. Pediatr Hematol Oncol. 2018;35(4):257–67. pmid:30537887
- 45. Aldrich KD, Horne VE, Bielamowicz K, Sonabend RY, Scheurer ME, Paulino AC, et al. Comparison of hypothyroidism, growth hormone deficiency, and adrenal insufficiency following proton and photon radiotherapy in children with medulloblastoma. J Neurooncol. 2021;155(1):93–100. pmid:34596831
- 46. Bishop AJ, Greenfield B, Mahajan A, Paulino AC, Okcu MF, Allen PK, et al. Proton beam therapy versus conformal photon radiation therapy for childhood craniopharyngioma: multi-institutional analysis of outcomes, cyst dynamics, and toxicity. Int J Radiat Oncol Biol Phys. 2014;90(2):354–61. pmid:25052561
- 47. Yip AT, Yu JD, Huynh-Le M-P, Salans M, Unnikrishnan S, Qian AS, et al. Post-treatment neuroendocrine outcomes among pediatric brain tumor patients: Is there a difference between proton and photon therapy? Clin Translat Radiat Oncol. 2022;34:37–41. pmid:35345865
- 48. Peterson RK, Katzenstein JM. Working memory and processing speed among pediatric brain tumor patients treated with photon or proton beam radiation therapy. Children’s Health Care. 2019;48:131–41.
- 49. Song S, Park HJ, Yoon JH, Kim DW, Park J, Shin D, et al. Proton beam therapy reduces the incidence of acute haematological and gastrointestinal toxicities associated with craniospinal irradiation in pediatric brain tumors. Acta Oncol. 2014;53(9):1158–64. pmid:24913151
- 50.
Nourah A, Daniel R, Nadine H. Characterization of Endocrinopathies in ChildrenTreated for Medullobalstomas.
- 51. Eaton BR, Esiashvili N, Kim S, Weyman EA, Thornton LT, Mazewski C, et al. Clinical outcomes among children with standard-risk medulloblastoma treated with proton and photon radiation therapy: a comparison of disease control and overall survival. international journal of radiation oncology*biology*physics. Int J Radiat Oncol Biol Phys. 2016;94(1):133–8. pmid:26700707
- 52.
Genevie`ve L, Akansha C, Jeffrey CA. Comparison of the incidence and time of onset of thyroid dysfunction in patients with medulloblastoma treated with proton or photon craniospinal irradiation.
- 53. Hong KT, Lee DH, Kim BK, An HY, Choi JY, Phi JH, et al. Treatment outcome and long-term follow-up of central nervous system germ cell tumor using upfront chemotherapy with subsequent photon or proton radiation therapy: a single tertiary center experience of 127 patients. BMC Cancer. 2020;20(1):979. pmid:33036578
- 54. Uemura S, Demizu Y, Hasegawa D, Fujikawa T, Inoue S, Nishimura A, et al. The comparison of acute toxicities associated with craniospinal irradiation between photon beam therapy and proton beam therapy in children with brain tumors. Cancer Med. 2022;11(6):1502–10. pmid:35137555
- 55.
Lassaletta A, Panizo E, Vazquez F, Serrano FJ, Carceller E, Gonzalez-San Segundo C, Aristu J, Calvo F. Proton versus photon craniospinal irradiation in Pediatric patients with high-risk medulloblastoma.
- 56. Sato M, Gunther JR, Mahajan A, Jo E, Paulino AC, Adesina AM, et al. Progression-free survival of children with localized ependymoma treated with intensity-modulated radiation therapy or proton-beam radiation therapy: Proton Therapy for Pediatric Ependymoma. Cancer. 2017;123(13):2570–8. pmid:28267208
- 57. Weusthof K, Lüttich P, Regnery S, König L, Bernhardt D, Witt O, et al. Neurocognitive Outcomes in Pediatric Patients Following Brain Irradiation. Cancers. 2021;13(14):3538. pmid:34298751
- 58. Ravindra VM, Okcu MF, Ruggieri L, Frank TS, Paulino AC, McGovern SL, et al. Comparison of multimodal surgical and radiation treatment methods for pediatric craniopharyngioma: long-term analysis of progression-free survival and morbidity. J Neurosurg Pediat. 2021;28(2):152–9.
- 59. Sparber‐Sauer M, Dietzschold M, Schönstein A, Heinz A, Vokuhl C, Pajtler KW, et al; the CWS Study Group. Radiotherapy and long‐term sequelae in pediatric patients with parameningeal rhabdomyosarcoma: results of two Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. Pediat Blood Cancer. 2024;71(1):e30742.
- 60. Marie Baunsgaard M, Sophie Lind Helligsoe A, Tram Henriksen L, Stamm Mikkelsen T, Callesen M, Weber B, et al. Growth hormone deficiency in adult survivors of childhood brain tumors treated with radiation. Endocr Connect. 2023;12(2):e220365. pmid:36507776
- 61. Unnikrishnan S, Yip AT, Qian AS, Salans MA, Yu JD, Huynh-Le M-P, et al. Neurocognitive outcomes in multiethnic pediatric brain tumor patients treated with proton versus photon radiation. J Pediatr Hematol Oncol. 2023;45(7):e837–46. pmid:37539987
- 62. Mash LE, Kahalley LS, Okcu MF, Grosshans DR, Paulino AC, Stancel H, et al. Superior verbal learning and memory in pediatric brain tumor survivors treated with proton versus photon radiotherapy. Neuropsychol. 2023;37(2):204–17. pmid:36480379
- 63. Friedrich C, Boekhoff S, Bischoff M, Beckhaus J, Sowithayasakul P, Calaminus G, et al. Outcome after proton beam therapy versus photon-based radiation therapy in childhood-onset craniopharyngioma patients—results of KRANIOPHARYNGEOM 2007. Front Oncol. 2023;13:1180993. pmid:37965466
- 64. Björk-Eriksson T, Glimelius B. The potential of proton beam therapy in paediatric cancer. Acta Oncol (Stockholm, Sweden). 2005;44(8):871–5. pmid:16332594
- 65. Breen WG, Geno CS, Waddle MR, Qian J, Harmsen WS, Burns TC, et al. Proton versus photon craniospinal irradiation for adult medulloblastoma: a dosimetric, toxicity, and exploratory cost analysis. Neurooncol. Adv. 2024;6(1):vdae034. pmid:38550393
- 66. Upadhyay R, Yadav D, Venkatesulu BP, Singh R, Baliga S, Raval RR, et al. Risk of secondary malignant neoplasms in children following proton therapy vs. photon therapy for primary CNS tumors: a systematic review and meta-analysis. Front Oncol. 2022;12:893855. pmid:36033525
- 67. Ludmir EB, Mahajan A, Paulino AC, Jones JY, Ketonen LM, Su JM, et al. Increased risk of pseudoprogression among pediatric low-grade glioma patients treated with proton versus photon radiotherapy. Neuro Oncol. 2019;21(5):686–95. pmid:30753704
- 68. Chung CS, Yock TI, Nelson K, Xu Y, Keating NL, Tarbell NJ. Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys. 2013;87(1):46–52. pmid:23778197
- 69. Trybula SJ, Youngblood MW, Kemeny HR, Clark JR, Karras CL, Hartsell WF, et al. Radiation induced cavernomas in the treatment of pediatric medulloblastoma: comparative study between proton and photon radiation therapy. Front Oncol. 2021;11:760691. pmid:34707999
- 70. Young S, Phaterpekar K, Tsang DS, Boldt G, Bauman GS. Proton radiotherapy for management of medulloblastoma: a systematic review of clinical outcomes. Adv Radiat Oncol. 2023;8(4):101189. pmid:37008255
- 71. Major N, Patel NA, Bennett J, Novakovic E, Poloni D, Abraham M, et al. The current state of radiotherapy for pediatric brain tumors: an overview of post-radiotherapy neurocognitive decline and outcomes. J Pers Med. 2022;12(7):1050. pmid:35887547
- 72. Doig M, Bezak E, Parange N, Gorayski P, Bedford V, Short M. Can we compare the health-related quality of life of childhood cancer survivors following photon and proton radiation therapy? A systematic review. Cancers. 2022;14(16):3937. pmid:36010929
- 73. Kim N, Lim DH. Recent updates on radiation therapy for pediatric optic pathway Glioma. Brain Tumor Res Treat. 2022;10(2):94–100. pmid:35545828
- 74. Berrington De González A, Gibson TM, Lee C, Albert PS, Griffin KT, Kitahara CM, et al. The pediatric proton and photon therapy comparison cohort: study design for a multicenter retrospective cohort to investigate subsequent cancers after pediatric radiation therapy. Adv Radiat Oncol. 2023;8(6):101273. pmid:38047226
- 75. Laprie A, Bernier V, Padovani L, Martin V, Chargari C, Supiot S, et al. Guide for paediatric radiotherapy procedures. Cancer/Radiothérapie. 2022;26:356–67.
- 76. Hegyi P, Petersen OH, Holgate S, Erőss B, Garami A, Szakács Z, et al. Academia Europaea position paper on translational medicine: the cycle model for translating scientific results into community benefits. J Clin Med. 2020;9(5):1532. pmid:32438747
- 77. Hegyi P, Erőss B, Izbéki F, Párniczky A, Szentesi A. Accelerating the translational medicine cycle: the Academia Europaea pilot. Nat Med. 2021;27(8):1317–9. pmid:34312557