Accepted on 06 Jun 2021
Submitted on 01 May 2021
Glioblastoma multiforme (GBM) remains the most common primary adult cerebral neoplasm, with an age-adjusted incidence rate of 3.22 per 100,000 population and a 5-year survival rate of 6.8% [1]. The current standard of care is maximal safe surgical resection, adjuvant radiotherapy and concomitant chemotherapy using temozolomide (TMZ), followed by 6 cycles of TMZ, as proposed by Roger Stupp and colleagues in 2005 [2]. This proposed treatment regimen has been demonstrated to result in a significant survival benefit compared to previous treatment methods [3, 4].
Despite the well-evidenced efficacy of Stupp protocol [2], the implementation of this approach bears an institutional and individual financial burden that is particularly notable in low- and middle-income countries (LMICs) [5]. Direct costs arise from the disease itself, relating to the economics of disease management. The introduction of the Stupp regimen increased direct GBM treatment costs eightfold compared to radiotherapy alone, from US$1,200 to US$4,600 per month [6, 7]. Additionally, indirect costs such as transportation, meals and housing during the treatment course augment the financial burden [8]. Given the implementation of well-funded public health institutions in high-income countries (HICs) (i.e. the National Health Service in the United Kingdom), the proportion of out-of-pocket (OOP) expenditure is minimal in HICs compared to that seen in LMICs [9]. Additionally, lack of access to radiotherapy services also hinders the ability of LMICs to adequately carry out the gold-standard treatment put forward by Stupp and colleagues [10].
The focus of research to date has centred on intra-country variability in GBM management outcomes [11]. To our knowledge, there is no literature evaluating inter-country variation in provision of optimal management for GBM, hence necessitating the need for a systematic review.
This protocol has been developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. The review was registered on the PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42020215843). Protocol amendments will be updated and published alongside the systematic review results (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=215843).
Adult patients (>18 years) with histologically confirmed primary unifocal GBM will be included. Paediatric and adolescent patients, as well as patients with multifocal, recurrent, relapsed, spinal or brainstem GBM will be excluded.
Evidence-based management of GBM, including surgery, chemotherapy, and radiotherapy, will be considered.
This review will consider studies that compare the efficacy of GBM treatment between HICs and LMICs as well as regional variations.
Studies that detail rates of complications, DALYs, prognosis, PFS, OS, abandonment of care and treatment delay will be included. Studies reporting health-related quality of life (HRQoL) measures as a primary outcome will be excluded.
Commentaries, original research, non-peer reviewed pieces, opinion pieces, editorials and case reports will be included. Conference abstracts, scoping/systematic reviews and book chapters will be excluded.
Studies written in English and French from 2005 to 2020 will be included in the review. Phase III and IV clinical trials and studies outlining the use of genomic sequencing as it relates to overall survival will also be included. Finally, studies focusing on sub-specialty training and fellowships within neuro-oncology will be included.
The databases to be searched include: MEDLine via Ovid, Embase and Global Index Medicus.
A search strategy has been developed to identify studies relating to the management of GBM and neuro-oncology training. Synonyms relating to OS, PFS, surgical intervention, chemoradiation therapy, resource limitation, treatment delay, abandonment of care and neuro-oncology education were used (Supplementary Figure 1).
The data records will first be downloaded from respective databases into EndNote X9. They will then be imported into COVIDENCE Systematic Review Software (Veritas Health Innovation, Melbourne, Australia) where deduplication, title and abstract screening as well as full-text screening will take place. Further data extraction and quality assessment will be carried out on Microsoft Excel (Microsoft, Richmond, Virginia, USA).
A calibration exercise will be carried out before title and abstract screening in order to ensure adequate understanding of the inclusion criteria by study screeners. Deduplication will be undertaken on COVIDENCE Systematic Review Software (Veritas Health Innovation, Melbourne, Australia). Each study will then be screened using title and abstract by 2 independent reviewers. Potentially eligible studies will be further screened for full-text review. Disagreements will be discussed amongst the reviewers and in the case of no resolution an appeal will be made to a third reviewer.
Full-text screened articles will be exported into a previously-made data extraction proforma on Microsoft Excel (Microsoft, Richmond, Virginia, USA). Data will be extracted on (i) study design, (ii) population, (iii) country of origin (iv) tumour characteristics, (v) treatment modalities, (vi) treatment adjuncts (vii) patient outcomes, (viii) abandonment of care, (ix) treatment delay and (x) neuro-oncology training. A short pilot extraction of 5 studies per reviewer will take place in order to assure the reliability of the proforma. Necessary changes will be made upon discussion in order to accurately capture the pertinent themes in the literature.
Two independent reviewers will conduct a risk of bias assessment. The Newcastle-Ottawa Scale (NOS) will be used for observational studies. Cochrane risk of bias 2.0 tool will be used for interventional studies. Conflict resolution will be conducted between the two reviewers, and in the case of no resolution an appeal will be made to a third reviewer.
A qualitative analysis of GBM management will be performed. The study design, type and the comparisons detailed in the study will be ascertained. Studies will primarily be dichotomised as either HIC or LMIC. Further sub-distinctions will be made based on geographical location if notable differences emerge in study findings. Pertinent characteristics of the study population will be analysed particularly relating to age, presence of risk-factors and comorbidities, all which contribute to the risk of being diagnosed with GBM and more importantly the subsequent outcomes. Particular features of the tumour will be noted, in order to gauge all the factors that have contributed to tumour prognosis in study participants, such as those related to tumour biology and tumour recurrence. The extent of surgical management for these tumours will be highlighted; a particular note will be taken as to whether these studies adhere to the recommended management of GBM proposed by Stupp et al [2], and reasons for falling short of this management protocol will be noted. Additionally, non-pharmacological therapies used in GBM treatment will also be determined, in order to assess the overall effectiveness of rehabilitation, education and other non-pharmacological therapies in the absence of adjuvant therapy, particularly in developing countries.
Four core treatment outcomes will be described: OS, PFS, DALYs and complication rates. An analysis of the treatment outcomes will enable a comparison of the treatment techniques between HICs and LMICs, as well as between two regions in the same financial bracket. The abandonment of care in studies will be assessed and reasons for abandonment will be outlined. Training programs in the regions of each study will be analysed, with a specific focus on the exposure to cases, the number of training hours and an analysis of any comments pertaining to the quality of these programs.
Finally, the delay in management of care will also be scrutinised using the three-delay model: delay in seeking, reaching, and getting care. Delay in care can be seen in a number of ways which can increase risk of morbidity and mortality. The number of these delays will be determined and possible solutions in order to correct these delays will be suggested.
This study will exclusively involve secondary data collection and no human participants will be involved in the design or dissemination of this research, hence ethical approval was not required. The results from this study will be disseminated through a peer-reviewed journal.
There is an extensive amount of literature published in Mandarin Chinese, Russian, and Portugese that will not be addressed by this review.
The proposed systematic review aims to detail the current landscape of GBM management worldwide, highlighting parallels and differences among countries in different income groups. This novel work will allow for a better understanding of the current situation in the developing world, where-in important lessons can be drawn from the robust learning environment in HICs, and vice-versa from the “out-of-box” thinking that is common in regions with limited resources. Despite the poor survival rate of patients with GBM, there are still pertinent lessons to be learnt to improve patient outcomes and the quality of care.
The additional file for this article can be found as follows:
Supplementary Figure 1MEDLine Search Strategy. DOI: https://doi.org/10.29337/ijsp.148.s1
Any amendments to this protocol will be prospectively updated on the PROSPERO International Prospective Register of Systematic Reviews.
GBM: Glioblastoma Multiforme
HICS: High-income countries
LMICS: Low and middle-income countries
TMZ: Temozolomide
OOP: Out-of-pocket
OS: Overall survival
PFS: Progression-free survival
DALYS: Disability-adjusted life-years
PRISMA-P: Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols
The authors have no competing interests to declare.
GA, USK and SB conceptualised the study. GA, USK, TP, AO, SB, AK, YZ, KM, SR drafted the initial manuscript. GA, REB and BV made critical revisions. All authors approved the final submission.
Conceptualization: Gideon Adegboyega, Ulrick Sidney Kanmounye, Soham Bandyopadhyay
Methodology: Gideon Adegboyega, Ulrick Sidney Kanmounye, Soham Bandyopadhyay
Supervision: Gideon Adegboyega, Ronnie E. Baticulon, Babar Vaqas
Writing-Orginal Draft: Gideon Adegboyega, Ulrick Sidney Kanmounye, Tatjana Petrinic, Ahmad Ozair, Soham Bandyopadhyay, Ashvin Kuri, Yvan Zolo, Katya Marks, Serena Ramjee
Writing- Reviewing & Editing: Gideon Adegboyega, Ronnie E. Baticulon, Babar Vaqas
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