Rehabilitation therapy for patients with glioma: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Glioma is the most common type of brain tumor because of the destructiveness of the disease itself and the side effects of treatment, patients often leave symptoms of neurological defects. At present, rehabilitation treatment is not popular in glioma patients. There is a lack of definite evidence to prove the benefits of rehabilitation therapy for glioma patients. The purpose of this meta-analysis is to determine whether rehabilitation therapy can significantly improve the prognosis of neurological function and improve the quality of life of patients with glioma.
METHODS: The articles about rehabilitation treatment of glioma in Cochrane, PubMed, and Embase, Web of Science, and Medline database from January 1990 to May 2020 were searched. Before rehabilitation as the control group, after rehabilitation as the experimental group. The Functional Independence Measure (FIM) was used as the outcome index, including total FIM, motor FIM, and cognitive FIM. Use STATA12.0 for meta-analysis.
RESULTS: A total of 8 articles were included in the study, with a total of 375 glioma patients. Meta-analysis of total FIM (SMD = 0.96, 95%CI = 0.66-1.26, P < .001), motor FIM (SMD = 0.75, 95%CI = 0.54-0.96, P < .001) and cognitive FIM (SMD = 0.35, 95%CI = 0.19-0.50, P < .001) indicated that the neurological function of rehabilitation was significantly improved in total, motor and consciousness.
CONCLUSION: The published studies show that rehabilitation therapy can improve the functional prognosis and quality of life of glioma patients. More attention should be paid to the therapeutic value of rehabilitation for glioma patients in the future. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020188740.

Introduction

Glioma is a tumor originating from brain glial cells, which is the most common in primary brain tumors.[ The World Health Organization (WHO) classifies gliomas as I-IV grade, of which low-grade gliomas (LGG) are I-II grade and high-grade gliomas (HGG) are III-IV grade.[ The disease has a certain risk of recurrence, especially in the high-level group. Including in situ recurrence, distant recurrence and spinal cord dissemination, and other special ways, of which in situ recurrence is the most common.[ The main clinical manifestations include increased intracranial pressure, epilepsy, neuromotor function, and cognitive impairment. The treatment is mainly surgical treatment, postoperative combined with radiotherapy and chemotherapy, and other comprehensive treatment. The disease requires the cooperation of neurosurgery, radiology, pathology, and rehabilitation medicine to adopt individual comprehensive treatment to achieve the best treatment benefit and improve the quality of life of patients.[ Tumor self-destruction and surgical treatment or postoperative radiotherapy and chemotherapy lead to obvious symptoms of neurological impairment in many patients.

Functional Independence Measure (FIM) was a functional assessment standard developed in the 1980s, which reflected the ability of daily life of the disabled more objectively and comprehensively, including self-care, sphincter control, mobility, locomotion, communication, and social cognition. There are 18 items in the above 6 categories. 1–7 points for each item, out of a total of 126 points. Motor FIM contains a total of 13 items in the first 4 categories, while cognitive FIM refers to a total of 5 items in the last 2 categories.[ FIM increases the content of cognitive and social aspects, and the evaluation of each item is more detailed, so it is more sensitive and accurate than the Barthel index in describing disability level and functional independence, closer to the overall goal of rehabilitation, and has better judgment consistency and reliability.[

Vincenzo Formica's previous meta-analysis of a Mono-Institutional Experience and 11 retrospective studies showed that neurological symptoms of patients with brain tumors increased by 36% after rehabilitation, but the study included not only gliomas but also meningiomas. At the same time, this study has been going on for almost 10 years.[ Currently, rehabilitation for glioma patients is recommended,[ but there is a lack of high-quality evidence to support this recommendation. there is a lack of definite evidence to prove that rehabilitation can improve the symptoms of neurological deficit and improve the quality of life in patients with glioma.[ The purpose of rehabilitation is to effectively improve the motor, consciousness, and psychology of glioma patients. However, it is a pity that the rehabilitation treatment for gliomas is not yet universal, especially for patients with high-grade gliomas.[ Therefore, it is necessary to conduct a new meta-analysis of the improvement of neurological function after the rehabilitation treatment of gliomas. We conducted a meta-analysis of the Total FIM, motor FIM, cognitive FIM included in the literature, hoping to comprehensively evaluate the effect of rehabilitation treatment on glioma patients from all aspects. And then to clarify the role of rehabilitation in glioma.

Materials and methods

Literature search strategy

A range of electronic databases was searched: PubMed, Embase, Web of Science, Cochrane, and Medline (from January, 1990 to May 2020). The following keywords and MeSH terms were used: Glioma, Gliomas, Glial Cell Tumors, Glial Cell Tumor, Tumor, Glial Cell, Tumors, Glial Cell, Mixed Glioma, Glioma, Mixed, Gliomas, Mixed, Mixed Gliomas, Malignant Glioma, Glioma, Malignant, Gliomas, Malignant, Malignant Gliomas Rehabilitation, Habilitation, functional outcome, etc. We also performed a manual search to find other potential articles.

The language of the article was English and the full text was available.

Only patients with gliomas were studied.

The study must provide data for the evaluation of complete function before and after rehabilitation treatment. The evaluation scale selected in this study is FIM, including Total FIM, Motor FIM, and Cognitive FIM.

Quality assessment

In this study, the data of the patients themselves before and after inclusion in the literature were extracted as control trials, which belonged to Non-randomized studies of the effects of interventions (NRSI). Risk of bias in non-randomized studies of interventions (ROBINS-I), a biased assessment tool, was selected to evaluate the quality of the literature. ROBINS-I was published in the British medical journal in October 2016.[ it was used to evaluate the effect of the intervention in a variety of non-random research types, a total of 7 areas were evaluated, and finally, Low risk of bias, Moderate risk of bias, Critical risk of bias, No information was obtained.

Data extraction

Two researchers read the full text of the literature together and then extracted the data from the relevant literature independently. If there are differences, we can reach an agreement through discussion or consult third-party experts to solve them. The contents extracted from each study included the name of the first author, year of publication, sample size, sex, age, WHO grade, type of FIM, FIM score at admission, and discharge. For some missing data in the article, we contacted the author and tried our best to obtain the original data. If the original author did not reply, Then the formula was calculated from other data provided in the literature.[

Ethical review

This study was a systematic review and meta-analysis, so ethical approval was abandoned and it was not necessary.

Statistics

FIM results of the treated cases (i.e., after rehabilitation) with those of the control group (i.e., before rehabilitation) as continuous variables, were expressed by mean and standard deviation, and then meta-analysis was carried out by Stata software. Observe whether the shapes of the funnel were symmetrical to judge the publication bias and further Egger test to evaluate the publication bias of the included literature (P ≤ .05 indicating that the publication bias is obvious). Q test and I2 test were used to evaluate the heterogeneity. I2 ≤ 50% indicated that there was no obvious heterogeneity, then a fixed effect model was used; if I2 > 50%, the random effect model was used to analyze the heterogeneity, and subgroup analysis was used to analyze the possible sources of heterogeneity. Sensitivity analysis determined whether the results were robust by observing the changes in the overall effect value after the deletion of a single study. The FIM score was described by the combined SMD, 95%CI. Using the Z test, the difference was statistically significant (P < .05).

Results

Literature retrieval results: 1405 related literature were initially retrieved, and 4 more literature were added through other channels, and the remaining 1222 were left after excluding 187 repetitive literature. After reading the abstract, 891 articles were excluded, including reviews, magazine letters, case reports, and so on.118 articles that could not obtain the full text, 113 were Irrelevant studies, 17 articles with incomplete outcome data, and 14 articles without accurate information of glioma were excluded. Finally, 8 articles were included in the meta-analysis, the specific content of which is shown in Figure 1.

Figure 1

The flow chart shows the study selection procedure. Eight studies were included in this meta-analysis.

A total of 375 glioma patients were recorded in 8 literature,[ including 201 males and 174 females. According to ROBINS-I, 5 articles were Moderate risk of bias, the other 3 were low risk of bias. In Julia's study, there were 2 groups of patients, including initial diagnosis of glioblastoma (iGBM) and recurrent glioblastoma (rGBM), so we included two groups of data.[ Fu's study provided two sets of data for LGG and HGG respectively.[ (Table 1)

Table 1

Characteristics of Studies Included in Meta-analyses.

Study	Year	Glioma grade	Male/ Female	Age (year, mean)	Functional index	Admission number	Admission score mean ± SD	Discharge number	Discharge score mean ± SD
Christina	2001	WHO (I-IV)	18/16	51.2	FIM	34	FIM motor = 41.2 ± 13.5	34	FIM motor = 55.7 ± 19.7
							FIM cogn = 21.1 ± 7.4		FIM cogn = 23.7 ± 6.2
Greenberg	2006	WHO (I-IV)	20/20	54.1	FIM	40	FIM total = 68.2 ± 24.2	40	FIM total = 80.7 ± 33.6
							FIM motor = 46.7 ± 30.9		FIM motor = 59.3 ± 36.6
							FIM cogn = 13.0 ± 6.7		FIM cogn = 13.3 ± 8.7
Vivien Tang	2008	WHO IV	8/10	61.4	FIM	18	FIM total = 85.3 ± 20.9	18	FIM total = 92.0 ± 19.3
							FIM motor = 52.7 ± 22.5		FIM motor = 66.3 ± 26.5
							FIM cogn = 31.3 ± 4.8		FIM cogn = 30.6 ± 7.2
Jack B.Fu	2010	WHO (I-II)	10/11	31.0	FIM	16	FIM total = 73.6 ± 17.3	16	FIM total = 86.6 ± 21.1
						20	FIM cogn = 25.1 ± 6.7	20	FIM cogn = 26.7 ± 6.3
		WHO (III-IV)	12/9	31.7	FIM	15	FIM total = 64.9 ± 11.1	15	FIM total = 86.6 ± 14.1
						18	FIM cogn = 20.4 ± 8.6	18	FIM cogn = 25.0 ± 7.0
Bartolo	2011	WHO IV	21/22	62.0	FIM	43	FIM total = 43.3 ± 16.5	43	FIM total = 72.5 ± 24.2
							FIM cogn = 20.9 ± 9.5		FIM cogn = 26.6 ± 7.1
Fary Khan	2014	WHO (I-IV)	22/31	53.1	FIM	53	FIM motor = 68.0 ± 10.7	41	FIM motor = 77.5 ± 14.2
							FIM cogn = 25.5 ± 4.2		FIM cogn = 30.5 ± 4.2
Pamela S	2014	WHO IV	58/37	62.5	FIM	95	FIM total = 54.2 ± 17.1	95	FIM motor = 73.9 ± 20.0
							FIM cogn = 18.9 ± 6.8		FIM cogn = 17.7 ± 7.0
Julia M	2020	WHO IV (iGBM)	17/8	61.6	FIM	25	FIM total = 55.4 ± 14.5	25	FIM total = 74.4 ± 23.4
							FIM motor = 33.7 ± 11.5		FIM motor = 48.6 ± 18.6
							FIM cogn = 19.5 ± 5.7		FIM cogn = 22.6 ± 10.2
		WHO IV (rGBM)	15/10	60.8	FIM	25	FIM total = 54.8 ± 14.5	25	FIM total = 78.5 ± 23.4
							FIM motor = 33.9 ± 11.5		FIM motor = 52.2 ± 18.6
							FIM cogn = 18.6 ± 5.7		FIM cogn = 22.6 ± 10.2

Meta-analysis results

The effect of rehabilitation on total FIM of glioma patients, 6 of the 8 articles included recorded 8 sets of complete data. Julia and Fu's studies contain two sets of data each. The heterogeneity among the studies was obvious (heterogeneity test: P = .016, I2 = 59.4%), so the random effect model was used. The results showed that rehabilitation treatment had statistical significance in improving total FIM score SMD = 0.96, 95%CI = 0.66–1.26 (P < .005). The heterogeneity was large, but there were less than 10 articles, so there was no Meta-regression analysis. According to the subgroup analysis of glioma WHO grade, we found that the high-grade glioma (HGG) subgroup I2 = 45.9% and the non-high-grade glioma (NHGG) including low-grade glioma group and mixed glioma group was heterogeneity I2 = 0.0%, indicating that the WHO grade of the tumor may be the source of heterogeneity. There were 5 articles providing 6 groups of data in motor FIM, 7 articles providing 9 groups of data in cognitive FIM. The study of Fu recorded the data of high-grade and low-grade glioma patients, while Julia recorded the data of primary GBM and recurrent GBM. The heterogeneity of motor and cognitive subscale of FIM were I2 = 13.7%, P = .327 and I2 = 0%, P = .546, respectively. Under the fixed-effect model, the Meta-analysis showed that the scores of motor FIM and cognitive FIM of rehabilitation treatment were SMD = 0.75, 95%CI = 0.54, 0.96 and SMD = 0.35 95%CI = 0.19, 0.50 respectively (P < .05). (Fig. 2A–C)

Figure 2

A. Forest plots for total FIM (HGG = high-grade gliomas; NHGG = non high-grade gliomas). B. Forest plots for motor FIM. C. Forest plots for cognitive FIM.

The shapes of the funnel were symmetrical (Fig. 3A–C). The results of the Egger test were shown in Table 2, indicating that there was no obvious publication bias in the three groups.

Figure 3

A. The shape of the funnel in total FIM group. B. The shape of the funnel in the motor FIM group. C. The shape of the funnel in the cognitive FIM group.

Table 2

Egger test for publication bias.

Type of test	Total FIM	Motor FIM	Cognitive FIM
Egger test (P)	P = .985	P = .418	P = .855

In the sensitivity analysis of 3 groups, no study was found to affect the total merger effect. (Fig. 4A–C)

Figure 4

A. The influence of a single study on the overall effect of total FIM. B. The influence of a single study on the overall effect of motor FIM. C. The influence of a single study on the overall effect of cognitive FIM.

Discussion

Gliomas are the most common brain tumor, accounting for 81% of brain malignant tumors, with an annual incidence of about 5.26 million. Glioma is a serious disease that endangers human health and affects the quality of life.[ Gliomas originate from neuroectoderm, including astrocytoma, oligodendroglioma, ependymoma, mixed glioma, and so on. The treatment is combined with radiotherapy and chemotherapy after surgical resection. With the application of functional magnetic resonance imaging and neuronavigation, the development of fluorescent chromogenic technology and bioengineering technology, the improvement of radiotherapy and chemotherapy, and the rapid progress of new therapies such as gene therapy and immunotherapy, the treatment of glioma has also made great progress. However, due to the strong invasiveness of the tumor itself, high recurrence rate, and poor prognosis, the average survival time is only 14 to 16 months.[

Due to the destruction of the disease itself and the side effects of treatment, most patients with gliomas have varying degrees of functional and psychosocial disorders, daily activities and social participation are limited, and the quality of life is reduced. Proper rehabilitation can improve the function of most patients. The purpose of rehabilitation for cancer patients is to enable them to improve their motor ability based on adapting to their physical state and strive to achieve self-care and let them live independently.[ At present, a large number of studies have confirmed that rehabilitation is of significance for the functional improvement of patients with brain tumors.[ However, there are some differences in the research results. Fary Khan found that during the follow-up of the effect of rehabilitation treatment in patients with primary brain tumors, the gain of 'sphincter’, and “cognitive” subscales was statistically significant, other subscales had no difference including motor.[ Pamela found that although rehabilitation treatment could not significantly improve the survival time of patients, it could improve the prognosis of most GBM patients, mainly in the field of the motor, but the improvement of disturbance of cognition and sphincter control was not significant.[ Tang found that patients with Glioblastoma multiforme (GBM) and intracranial metastases tended to show longer survival if their FIM scores increased significantly after rehabilitation.[ It can be seen that rehabilitation therapy has different views on the improvement of disturbance of cognition and survival time of glioma. Studies on cognition, have shown that rehabilitation therapy was less efficient for glioma patients than stroke patients, because stroke patients had more damage to this area, so they would get better gain in this area.[ Cognitive impairment was not conducive to the rehabilitation of patients, the mental state of admission was poor, the rehabilitation effect was also poor, there was a significant positive correlation.[ Besides, there were individual differences in the degree of patients’ response to rehabilitation intervention. For the selection of people with rehabilitation effect, researchers had also conducted some studies, the degree of fatigue was an independent risk factor affecting the prognosis,[ and disturbance of cognition was an independent risk factor affecting the survival of patients.[ The evidence suggested that exercise behavior was an independent predictor of survival in patients with high-grade gliomas,[ but there was still a lack of conclusive evidence that improved mobility could improve patient survival. Some hypotheses could help explain why improving patients’ exercise ability to improve patient survival. For example, the motor could reduce the risk of complications such as deep venous thrombosis and pulmonary infection; there was evidence that exercise could improve the tumor microenvironment by regulating cytokines.[

In this study, the results show that rehabilitation treatment could significantly improve the quality of life of glioma patients, including the improvement of motor and cognition. Besides, this study used the method of the subgroup to analyze the source of heterogeneity in the total FIM group and concluded that WHO classification was the source of heterogeneity. It is generally believed that high-grade gliomas are seriously invasive and rehabilitation therapy may not be effective in improving neurological function, but some studies have pointed out that the destruction of brain tissue is not an important factor affecting the effect of rehabilitation.[ Fu's study on the rehabilitation effect of different grades of gliomas found that in the high and low-grade gliomas, the functional improvement after rehabilitation treatment was statistically significant, and rehabilitation treatment could make high-grade glioma patients get higher neurological function gain, but their hospital stay was significantly longer than that of low-grade glioma patients.[ Piil pointed out that rehabilitation was beneficial to improve patients’ neurological prognosis, memory, and stress relief, and suggested that clinical guidelines for rehabilitation be developed for patients with high-grade gliomas.[ Our result analysis also showed that even in the high-grade glioma group, the FIM score was significantly improved after rehabilitation.

There are some limitations in this study; first of all, because ROBINS-I was published recently and the operation is complex, there is no convenient software for evaluation, so it is difficult for beginners to make a completely correct evaluation for inclusion in the literature. Second, we chose a traditional method function independence measurement, which may not be comprehensive enough to evaluate the functional prognosis of patients. In some studies,[ the exercise rating scale (MAS), Stroke posture rating scale (PASS) and Berg balance scale (BBS), depression, anxiety stress scale, perceived impact problem profile and cancer rehabilitation evaluation system, Massachusetts General Hospital Functional Ambulation Classification, Standing Balance score, Sitting Balance score, Hauser Index and so on were added to evaluate the functional recovery more accurately and comprehensively.[ Our study has not yet determined whether rehabilitation can prolong the survival of glioma patients.

Conclusion

The published studies show that rehabilitation therapy can improve the functional prognosis and quality of life of glioma patients. More attention should be paid to the therapeutic value of rehabilitation for glioma patients in the future.

Author contributions

Conceptualization: Ninghui Zhao

Data curation: Chaojun Yu, Zhichao Gan, Tingting Wu

Formal analysis: Kai Zhao, Chaojun Yu

Funding acquisition: Ninghui Zhao

Investigation: Kai Zhao

Methodology: Kai Zhao, Minhao Huang

Supervision: Ninghui Zhao

Writing – original draft: Kai Zhao

Writing – review & editing: Kai Zhao, Ninghui Zhao