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Research Article | DOI: https://doi.org/10.31579/2578-8868/207
1 Department of Neurosurgery, Wuhan Children’s Hospital(Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
2 Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China.
3 Department of pediatrics, Laizhou Maternal and child Health care hospital, Yantai, China.
*Corresponding Author: Weiping Zhan, Spinal Unit, Department of pediatrics, Laizhou Maternal and child Health care hospital, Yantai, China.
Citation: Wenyue Deng, Mingyang Liu, Shiyuan Jing, lingling Zhang, Xuhui Liu, Weiping Zhan. (2022) Efficacy and Safety of Proton Therapy for Medulloblastoma Patients: A Mata-Analysis. J. Neuroscience and Neurological Surgery. 11(2); DOI:10.31579/2578-8868/207
Copyright: © 2022 Weiping Zhan, 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
Received: 15 October 2021 | Accepted: 04 November 2021 | Published: 04 January 2022
Keywords: proton radiotherapy; medulloblastoma; efficacy; safety; meta-analysis
Background: Currently, photon therapy is mainly used for radiotherapy, however, the long-term side effects of photon therapy are sometimes reported, especially in children, including cognitive decline, mental decline, growth retardation, endocrine dysfunction and secondary tumor.Compared with photon radiotherapy, proton therapy is a novel method of radiation therapy, which reduces acute and late radiation damage and improves patients’ quality of life. Therefore, we evaluated proton therapy on medulloblastoma patients by meta-analysis in this study.
Materials and Methods: A clinical randomized controlled trial was conducted by retrieving the main databases PubMed (Medline), EMbase, Cochrane Library, Chinese Biomedical Literature Database (CBM), Chinese Zhi-wang (CNKI), Wanfang Database, and VIP Database. We analyzed the literature which matched the quality criteria for the prognostic impact of proton and photon therapy on medulloblastoma patients.
Results: Ten articles were included in this study. The overall survival (OS) rate and side effects were comprehensively analyzed. The results showed that proton radiotherapy significantly reduced the side effects and recurrence rate of tumor.
Conclusion: Proton therapy could significantly reduce the side effects and recurrence rate of medulloblastoma in patients.
The current treatment strategy of medulloblastoma is surgery combined with radiotherapy and adjuvant chemotherapy [1]. The 5-year overall survival (OS) rate is close to 85% at standard risk, however, the high-risk patients are approximately 70%[2].Compared with photon radiotherapy, proton therapy is a novel method of radiation therapy, which could accurately kill tumor cells and protect the organs around the tumor. Moreover, the therapy reduces side effects and improves quality of life. With the development of proton therapy, an increasing number of medulloblastoma patients are receiving the therapy method [2].
The study of medulloblastoma proton therapy was in conformity to the principle of randomization [3,4], mainly involving observational studies with a lower level of evidence in randomized controlled studies. This study systematically collected literature of proton therapy on medulloblastoma patients, and evaluated its efficacy and safety.
1 Methods
1.1 Criteria for inclusion and exclusion of literature
1.1.1 Inclusion criteria: ①Research types: Observational studies published in China and abroad, Chinese and English literature.②Medulloblastoma confirmed by pathology, without limitation in T/M staging. No contraindication to radiotherapy, unlimited age or gender. ③The traditional photon radiation therapy as the control group, and the proton therapy as the experimental group.
1.1.2 Exclusion criteria: ①The study type was not clearly declared, and research data was not provided. ②Repeatedly published literature. ③The study could not meet the inclusion criteria. ④The sample size was less than 10 cases. ⑤There were no defined outcome and efficacy evaluation criteria. ⑥Summary, case report, lecture and review were excluded.
1.2 Outcome indicators
1.2.1 Primary outcome indicators: ①OS was defined as the time interval from the date of diagnosis to date of death or the last follow-up for survivor. ②Recurrence free survival (RFS) was defined as the time from complete remission until recurrence or the last follow-up.
1.2.2 Secondary outcome indicators: ①Late complications: ototoxicity, neuroendocrine toxicity including neuroendocrine (growth hormone and thyroid hormone) deficits and neurocognitive (intelligence, reasoning, memory) deficits. ②Early and late toxicity included alopecia, fatigue, anorexia, stroke, cataract, obesity, etc.
1.3 Retrieval Strategy
All observational studies on postoperative proton therapy of medulloblastoma patients from January 1992 to March 2020 were retrieved by computer in PubMed, EMbase, Cochrane library, CBM, CNKI, Wanfang database, and VIP database, by MeSH of "Proton Radiotherapy, Medulloblastoma, cohort studies". In addition, references, conferences and network information were manually retrieved from the related literature.
1.4 Literature screening
Mingyang Liu and wenyue Deng independently screened these literature, extracted and cross-checked the data. weiping Zhan included or excluded the literature, if there were inconsistencies. The substandard literature was excluded by the subject and abstract, and then further determined by reading the full text.
1.5 Data extraction
(1) The basic information included in the literature: study type, author, publication year, etc. (2) The basic characteristics of the subjects: sample size, age, sex, grade, resection degree, follow-up time, etc. (3)Total and fractionated doses of proton therapy. (4) Efficacy and safety outcome.
1.6 Literature quality evaluation
A total of 10 articles were included by rigorous screening, including 4 retrospective case-control studies and 6 observational studies. The statistical method was scientific and reasonable, and articles with complete data underwent data extraction. The Newcastle-Ottawa Scale (NOS) was used to evaluate the literatures. All retrospective cohort studies had NOS scores≧6. The quality evaluation of high-quality literature was completed independently by shiyuan Jing. The final scores were determined by shiyuan Jing.
1.7 Statistical analyses
Review Manager 5.3 and STATA12.0 software were used to analyze the data, and descriptive analyses were performed to analyze the outcome indicators that could not be combined. Firstly, the heterogeneity was evaluated. According to the Cochrane System Evaluation Guide, the heterogeneity significance level was set at P=0.1 and I2=50%. When P>0.1 and I2≦50%, the heterogeneity between the results was not statistically significant, and the fixed effect was used to analyze the heterogeneity. When P<0>50%, there was heterogeneity in the results. The causes of heterogeneity could be found by subgroup analysis, sensitivity analysis and meta-regression analysis. If the cause was not ascertained and the degree of heterogeneity was acceptable, random effects were selected for data consolidation. The funnel map was used to identify bias in the primary outcome.
2.1 According to the retrieval strategy, 56 articles were retrieved. Based on the exclusion criteria, 10 articles were analyzed scrupulously in the study, and the document screening process was shown as follows (Figure 1).
2.2 Basic characteristics of the literature
Four articles were retrospective case-control studies, and six articles were observational studies. 492 patients were treated with proton therapy, while 180 patients were treated with photon therapy.
2.3 Results of meta-analysis
There was 1, 4 and 1 articles that reported 3-, 5- and 7-year OS respectively. One non-randomized controlled trial reported that 5-year OS was 82.0% for proton therapy and 87.6% for photon therapy. One observational study reported that 3-year OS was 85.6% for proton therapy, and another observational study reported that 7-year OS was 81% for proton therapy.
Firstly, the heterogeneity were examined for 5-year OS in four articles (I2=98% and P<0>
The meta-analysis showed that 85% of the total effects were statistically significant by random effects (Z=6.51, P<0>
Meta-analysis based on random effect indicated that there was no deviation in the study, and further symmetry test showed P>0.05, suggesting that there was no publication bias in this study (Figure 3).
Progression-free survival (RFS) was reported in 1 and 3 articles for 3- and 5-year OS respectively. A nonrandomized controlled trial reported that the RFS of proton therapy and photon therapy was 78.8% and 76.5% respectively for medulloblastoma. One observational study reported that the 3-year RFS of proton therapy was 83%.
Firstly, 5-year RFS examined heterogeneity in three articles (I2 =0 and P>0.1) (Figure 4), suggesting no heterogeneity between the literature, and that the fixed effect could be selected for meta-analysis. Sensitivity analysis was then performed to ensure the accuracy and stability. The sensitivity analysis was carried out in three articles, and none had obvious effect on the results, revealing good stability of the study.
Meta-analysis showed that the 79
Ten articles were included in the study, and a total of 492 medulloblastoma patients underwent proton therapy. The results showed that the OS of proton therapy was higher than that of photon therapy. The study suggested that proton therapy was effective on OS and RFS for medulloblastoma patients.
Proton therapy can precisely plan the target area and cover the tumor foci, which protects normal brain tissue and ensures sufficient dose of radiation [5-7]. Meta-analysis showed that side effects of proton therapy included endocrine dysfunction, impaired speech processing speed and comprehension, hearing impairment.
Literature studies showed that proton group was superior to photon group in central/primary hypothyroidism [8, 9]. Compared with photon therapy, the risk of sex hormone deficiency was apparently reduced (3% vs. 19%, P<0>0.05).
Parents reported 59.1 health core scores, which was increased by 2.0 points per year [10]. These scores were significantly improved in proton therapy group, suggesting that proton therapy could continuously improve children’s quality of life. The meta-analysis reported 1.5 point reduction per year in language processing speed and comprehension, while there was no significant difference in cognitive reasoning index and memory [11].
Benjamin J Moeller [12] had shown that hearing sensitivity decreased significantly in frequency ranges by proton therapy. The hearing threshold was partially reduced after radiotherapy, and the incidence of ototoxicity (grade 3 or 4) was 5% at 1 year after treatment.
This study has several limitations. First, the clinical effect of medulloblastoma in children was not evaluated by progression-free survival and recurrence survival, but by 5-year OS and RFS, and few literatures are available. Second, proton dose and fractionation were different in the study, including preoperative risk grade, resection degree, and chemotherapy, therefore, it was impossible to conduct a more detailed stratified comparative study. We will perform stratified analyses to pinpoint the independent prognostic factors and pathological characteristics which could affect the prognosis in medulloblastoma patients.Finally, different molecular types have different sensitivity and effectiveness to radiotherapy, and few studies have reported the meta-analysis to date. The influence of molecular types on radiotherapy efficacy should be paid more attention to subsequent case-control studies in the future.
To date, proton therapy is a safe and feasible method in medulloblastoma, which could improve the survival rate and RFS rate, and has fewer side effects than photon therapy. Clinical studies with high quality and a large sample size are needed before proton therapy is applied to medulloblastoma patients.
In brief, proton therapy is preferred radiotherapy for postoperative children with medulloblastoma.
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