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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 7  |  Page : 2058-2065

Meta-analysis of neurocognitive rehabilitation for cognitive dysfunction among pediatric cancer survivors


1 Neonatal Intensive Care Unit, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
2 Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, China

Date of Submission08-Jul-2022
Date of Decision05-Sep-2022
Date of Acceptance14-Oct-2022
Date of Web Publication11-Jan-2023

Correspondence Address:
Xiulan Wen
No. 9, Jinsui Road, Tianhe District, Guangzhou
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_1429_22

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 > Abstract 


Cancer and its treatment significantly affect the cognitive functioning of pediatric cancer survivors. This meta-analysis aimed to examine the effects of neurocognitive rehabilitation interventions on the cognitive functioning and intellectual performance of pediatric cancer survivors. Four databases were searched until December 15, 2021. RevMan 5.4 was used to analyze the effects of neurocognitive rehabilitation interventions on the cognitive functioning of pediatric cancer survivors. Ten eligible randomized controlled trials were initially identified, and nine of these were included in the meta-analysis. For the working memory outcome, the pooled effect results favored study interventions and had statistical significance at postintervention assessment (Z = 2.24, P = 0.03). For the attention outcome, there were significant statistical differences at postintervention and 3/6-month follow-up assessment (Z = 2.72, P = 0.007 and Z = 10.45, P < 0.001, respectively). For the executive functioning outcome, there were significant statistical differences at postintervention and 3/6-month follow-up assessment (Z = 2.90, P = 0.004 and Z = 14.75, P < 0.001, respectively). For the academic/intellectual performance secondary outcome, the pooled overall effects of study interventions on the academic/intellectual outcome were positive at postintervention and follow-up assessment (Ps < 0.001). No studies reported any adverse events related to neurocognitive and educational interventions. This meta-analysis found that neurocognitive rehabilitation interventions improve the working memory, attention, and executive functioning of pediatric cancer survivors at postintervention and short-term follow-up. Neurocognitive rehabilitation also has positive effects on the academic/intellectual performance of this study population during a vulnerable period in their development.

Keywords: Cognitive functioning, meta-analysis, neurocognitive rehabilitation, pediatric cancer survivors


How to cite this article:
He F, Huang H, Ye L, Wen X, Cheng AS. Meta-analysis of neurocognitive rehabilitation for cognitive dysfunction among pediatric cancer survivors. J Can Res Ther 2022;18:2058-65

How to cite this URL:
He F, Huang H, Ye L, Wen X, Cheng AS. Meta-analysis of neurocognitive rehabilitation for cognitive dysfunction among pediatric cancer survivors. J Can Res Ther [serial online] 2022 [cited 2023 Jan 27];18:2058-65. Available from: https://www.cancerjournal.net/text.asp?2022/18/7/2058/367461




 > Introduction Top


More than 400,000 children worldwide are diagnosed with cancer annually, and a child is diagnosed with cancer every 3 min.[1] In high-income countries, such as the United States, the estimated 5-year net survival rate for pediatric cancers is 79.85%, and the global 5-year survival rate is 56%.[1] Among all types of pediatric cancer, the two most common forms are brain tumors and acute lymphoblastic leukemia (ALL).[2] With an increased number of pediatric cancer survivors, two-thirds of this cancer survivor population report at least one cancer-related sequela, such as cognitive dysfunction,[3],[4],[5] which can adversely affect their health and academic development/growth.[3],[6]

Previous research has estimated that one-third of pediatric cancer survivors report cognitive dysfunction.[7] Among pediatric brain tumor survivors, the prevalence of cognitive dysfunction is as high as 50%–80%.[8] Cognitive dysfunction includes various aspects of impairment in working memory, attention, executive functioning, and information processing speed, all of which have negative effects on the learning abilities, academic achievement, and long-term development of pediatric cancer survivors, including their educational and employment attainment.[2],[8],[9] Neurocognitive rehabilitation interventions effectively diminish cognitive dysfunction among pediatric cancer survivors.[2],[10],[11],[12],[13] These intervention programs utilize cognitive and/or behavioral skills acquisition approaches demonstrated to improve the cognitive functioning and academic achievement of pediatric cancer survivors.[2]

One meta-analysis compared the academic/intellectual outcomes of pediatric cancer survivors with ALL to those of controls without a history of cancer.[14] In terms of study subjects, this meta-analysis only included pediatric cancer survivors with ALL. In terms of study types, it only included observational studies and failed to include any intervention study.[14] Krull et al.[2] provided a comprehensive review of all aspects of cognitive dysfunction, including the prevalence and pattern, associated factors, neurochemical biomarkers of cognitive deficits, cognitive outcome assessment, and possible interventions, to facilitate rehabilitation for long-term pediatric cancer survivors, including survivors of the two most common cancer types, namely brain tumor and ALL. However, this review did not quantify the effects of neurocognitive rehabilitation programs on the cognitive and academic outcomes of pediatric cancer survivors.

Therefore, this current meta-analysis aimed to examine the effects of neurocognitive rehabilitation interventions on the cognitive functions of pediatric cancer survivors and whether cognitive remediation interventions improve the academic/intellectual performance of this study population.


 > Subjects and Methods Top


Search strategy and data resources

This meta-analysis involved a literature search in four electronic databases—PubMed, EMBASE, Scopus, and PsychINFO—until December 15, 2021. The search terms used a combination of keywords and medical subject headings. The search strategies are listed in Appendix 1.

Eligibility criteria

Studies involving pediatric patients and/or survivors with brain tumors or ALL were included in this meta-analysis, as these are the most common types of childhood cancer. In line with the conventional age-related definition, pediatric cancer survivors were defined as children ages <18 years. The examined interventions included all neurocognitive rehabilitation programs, such as neurocognitive and psychoeducational interventions. The controls included standard/usual care, waitlist controls, and other supportive care interventions. The primary outcomes included cognitive outcome measures, and the secondary outcomes included academic/intellectual outcomes and any adverse effects directly related to interventions. In terms of study types, only randomized controlled trials (RCTs) were included.

Data extraction

Two of the authors (X.W. and F.H.) independently conducted data extraction for each RCT. Both authors mainly extracted the characteristics, including key information about the study population, interventions, outcome measures, and the results of primary and secondary outcome measures at postintervention and follow-up assessments. If there was any disagreement involving data extraction, the final author of this manuscript (A.S.K.C.) was always involved in the discussion to achieve agreement.

Risk of bias assessment

The study used the Cochrane Risk of Bias Assessment tool[15] for the methodological quality assessment. The steps in the assessment were similar to those in the data extraction process. Two authors (L.Y. and H.H.) conducted the risk of bias assessment for each included RCT independently, and any disagreements were discussed with the third author (Y.L.) to reach a consensus.

Data synthesis and analysis

The Cochrane Collaboration's Review Manager (RevMan 5.4) was used for quantitative data synthesis and estimating the pooled effects of study interventions.[15] If data for standard deviations were missing, they were calculated using standard errors or other related information, such as 95% confidence intervals (95% CIs), using the RevMan Calculator.[16] The heterogeneity of the included trials was calculated with χ2 test and I2 statistics. P <0.1 (χ2) and I2 > 50% are indicators of statistical heterogeneity.[17] If an obvious indication of heterogeneity occurred, the estimations of the intervention effect size were made using the random-effects model; otherwise, the estimation of the intervention effect size was made using the fixed-effects model. The pooled effects of study interventions were assessed using P < 0.05, indicating statistical significance.


 > Results Top


The methodology of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 was followed.[18] [Figure 1] presents the full study selection procedure. In total, 10 of 125 extracted studies were initially selected for the meta-analysis. However, 1 of these 10 studies was a pilot RCT without sufficient information for pooling study outcomes;[19] so, only nine RCTs were included in this meta-analysis.[10],[11],[12],[20],[21],[22],[23],[24],[25]
Figure 1: PRISMA 2020 flow diagram of the study selection

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Characteristics of included studies

[Table 1] presents the characteristics of nine RCTs included in the meta-analysis. Data were organized under the headings of author and year, study participants, study interventions, outcome measures, and major findings. The number of study participants varied from 20 to 161. The age ranges of pediatric cancer survivors were mainly from 6 to 18 years. Of the nine RCTs, six adopted cognitive training interventions, whereas the remaining three used the following types of intervention: cognitive rehabilitation, neurofeedback, and education. The key cognitive outcome domains included working memory, attention, and executive functioning. Academic/intellectual performance was mainly measured by the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV; [Table 1]).
Table 1: Characteristics of the included nine RCTs

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Quality of study methods

[Figure 2]a presents a summary of the risk of bias assessment, and [Figure 2]b presents the bias assessment risk of each RCT. Overall, all nine included RCTs had a low risk of bias. Only in the domain of blinding study subjects or research personnel did these studies have a high risk of bias. Of the nine included trials, only one used a strategy to blind the study subjects and/or research personnel by providing two versions of the intervention program, which varied from the levels of the intervention dose.[10]
Figure 2: (a) Summary of risk of bias assessment. (b) Risk of bias assessment of each RCT

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Effects of study interventions on primary outcomes

In terms of primary outcomes, all included trials reported improvements in cognitive outcomes, including working memory, attention, and executive functioning. In [Figure 3]a to [Figure 3]c, comparisons of the working memory outcome reported that the pooled effects were in favor of study interventions; however, there was only statistical significance at postintervention assessment (Z = 2.24, P = 0.03; [Figure 3]a). The changes in scores for working memory and follow-up assessment of working memory at 3/6-month follow-up had no statistical significance (Z = 1.70, P = 0.09 and Z = 1.45, P = 0.15, respectively, [Figure 3]b and [Figure 3]c). In terms of the attention outcome, there were significant statistical differences at postintervention and 3/6-month follow-up assessment [Figure 4]a and [Figure 4]b. Six trials assessed the effects of neurocognitive interventions on pediatric cancer survivors' attention at postintervention; the reported standard mean difference (SMD) was 0.81 (95% CI, 0.23–1.40; Z = 2.72, P = 0.007; [Figure 4]a). Three trials reported attention outcomes at follow-up; the reported weighted mean difference (WMD) for the attention outcome was 1.38 (95% CI, 1.12–1.64) at 3/6-month follow-up [Figure 4]b. In terms of executive functioning outcomes, six trials assessed the effects of neurocognitive interventions on pediatric cancer survivors' executive functioning at postintervention, with an SMD of 1.06 (95% CI, 0.34–1.77; Z = 2.90, P = 0.004; [Figure 5]a), and three trials assessed executive functioning outcomes at follow-up, with a WMD of 1.76 (95% CI, 1.53–2.00) at 3/6-month follow-up [Figure 5]b.
Figure 3: (a) Working memory at postintervention assessment. (b) Working memory at 3/6-month follow-up assessment. (c) Change in working memory from postintervention to follow-up assessment

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Figure 4: (a) Attention at postintervention assessment. (b) Attention at 3/6-month follow-up assessment

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Figure 5: (a) Executive functioning at postintervention assessment. (b) Executive functioning at 3/6-month follow-up assessment

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Effects of study interventions on secondary outcomes

In terms of secondary outcomes, all included trials reported improvements in academic/intellectual performance at postintervention and 3/6-month follow-up. Six RCTs compared the academic/intellectual outcomes for pediatric cancer survivors, with a WMD of 3.36 (95% CI, 3.09–3.64; [Figure 6]a), and there were five trials involving 391 subjects that examined the effects of study interventions on academic/intellectual outcomes, with a WMD of 1.67 (95% CI, 1.40–1.94; [Figure 6]b). None of the studies reported adverse events related to neurocognitive and educational interventions.
Figure 6: (a) Academic/intellectual performance at postintervention assessment. (b) Academic/intellectual performance at 3/6-month follow-up assessment

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 > Discussion Top


This meta-analysis summarizes direct comparisons of the effects of neurocognitive rehabilitation interventions on objective cognition and intellectual outcomes for pediatric cancer survivors. Neurocognitive rehabilitation consists of cognitive remediation, compensation, and education components.[2] The pooled intervention effect size ranged from 0.81 to 3.86 postintervention. The age range of pediatric cancer survivors in this study was 6 to 18 years. During this critical stage of brain development, any insult from central nervous system lesions or toxic agents, such as chemotherapy, to the developmental neural networks of the brain would have a more severe and dynamic effect on the pediatric brain than it would on the brain of an adult cancer survivor.[26]

A previous review summarized all possible interventions for cognitive dysfunction in pediatric cancer survivors.[2] This meta-analysis provides additional quantitative evidence on the effects of neurocognitive rehabilitation interventions in managing the cognitive outcomes of pediatric cancer survivors. As indicated by Hocking et al.,[23] cognitive remediation with pediatric cancer survivors is a burgeoning area, and innovative intervention approaches are needed to enhance pediatric cancer survivors' cognitive outcomes. Indeed, technology-enabled interventions would increase their accessibility to cancer survivors.[27] A recent review recommended integrating machine learning and blockchain technologies into cancer care.[28] Hopefully, future research can apply these two most promising technologies to cognitive dysfunction management for pediatric cancer survivors, as globally there is an obvious trend of incorporating cutting-edge technologies into cancer care.

Although neurocognitive rehabilitation had positive effects on cognitive and intellectual outcomes in pediatric cancer survivors, the rehabilitation mechanism is largely unknown. Kesler et al.[13] conducted a single-arm trial of a cognitive rehabilitation program with pediatric cancer survivors and explored the possible intervention mechanism of this program on the cognitive dysfunction of this study population. This study suggested a possible rehabilitation mechanism that changes functional brain networks and enhances functional brain connectivity.[13] Some intervention research on adult cancer survivors also confirmed this possible rehabilitation mechanism.[29],[30] Van der Gucht et al.[31] examined the effects of a mindfulness intervention on cancer-related cognitive impairment and explored the potential mechanism in adult survivors of breast cancer. They found that a mindfulness intervention has positive effects in terms of improving the cognitive functioning of adult cancer survivors and possibly enhancing the functional connectivity between dorsal and salience attention networks. Therefore, more research is required to explore the possible mechanisms of neurocognitive interventions in managing cognitive dysfunction and develop precision intervention strategies for ameliorating cognitive dysfunction among pediatric cancer survivors.

The limitations of this meta-analysis should be considered. The sample sizes in most RCTs in the meta-analysis were relatively small (20–161 subjects), thus limiting the generalizability of the findings. Most of the nine included trials conducted a short-term follow-up assessment of cognitive and intellectual outcomes. Hence, the long-term effects of neurocognitive rehabilitation interventions on pediatric cancer survivors are largely unknown. This, in part, may be due to practical issues, including limited available resources and a limited time frame for conducting the original study. Yet, future research should explore long-term changes among pediatric patients as a result of neurocognitive rehabilitation interventions for cognitive dysfunction.


 > Conclusion Top


This meta-analysis found that neurocognitive rehabilitation interventions improve the working memory, attention, and executive functioning of pediatric cancer survivors at postintervention and short-term follow-up. Neurocognitive rehabilitation also has positive effects on this study population's academic/intellectual performance during a vulnerable period in their development. Future research assessing long-term outcomes and employing larger sample sizes could confirm these positive effects of neurocognitive interventions for pediatric cancer survivors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


 > Appendix 1 Search Strategy in Databases Top


PUBMED/EMBASE/SCOPUS/PSYCHINFO search strategy

  1. exp Neoplasms/or exp Bone Marrow Diseases/or exp Bone Marrow Transplantation/or exp Stem Cell Transplantation/or exp Radiotherapy/or exp Chemotherapy, Adjuvant/or exp Antineoplastic Combined Chemotherapy Protocols/or exp Salvage Therapy/or exp Palliative care/
  2. (neoplasms* or cancer* or tumour* or tumor* or malignan* or carcino* or lymphoma* or adenocarcinoma* or radioth* or radiat* or irradiat* or radiochemo* or chemotherap* or (bone adj marrow adj5 transplant*)).mp.
  3. 1 or 2
  4. exp cognitive impairment
  5. (cognitive dysfunction* or “cognition disorders”[Mesh]) or cognition disorders)).mp.
  6. 4 or 5
  7. exp psychology, social/or exp psychotherapy
  8. (psychosocial$ or psycho-social$).mp.
  9. (counsel$ or (behaviour$ adj4 therap$) or “training” or (behavior$ adj4 therap$) or (relax$ adj4 therap$) or (relax$ adj4 treatment$) or (support$ adj4 group$) or imagery or “energy conservation” or “stress management” or psychotherapy$ or “self-care” or “self-help” or biofeedback or educati$ or psychoeducat$ or relaxation therap$ or “nursing intervention” or “nursing support”).mp.
  10. 17. or 7-9 (Psychosocial Interventions)
  11. Randomized controlled trial.pt.
  12. controlled clinical trial.pt.
  13. pediatric*
  14. childhood
  15. or 11-14.




 
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  [Full text]  
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