Current State of Health Economic Analyses for Low-Grade Glioma Management: A Systematic Review.

BACKGROUND: Health economic analyses help determine the value of a medical intervention by assessing the costs and outcomes associated with it. The objective of this study was to assess the level of evidence in economic evaluations for low-grade glioma (LGG) management. METHODS: Following the PRISMA guidelines, we conducted a systematic review of English articles in Medline, Embase, The Central Registration Depository, EconPapers, and EconLit. The results were screened, and data were extracted by 2 independent reviewers for studies reporting economic evaluations for LGG. The quality of each study was evaluated using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) checklist, the hierarchy scale developed by Cooper et al. (2005), and the Quality of Health Economic Studies instrument. RESULTS: Three studies met our inclusion criteria. The adjusted incremental cost-effectiveness ratio (ICER) values for the included studies ranged from $3934 to $9936, but each evaluated a different aspect of LGG management. All had a good quality of reporting per the CHEERS checklist. Based on the Cooper et al. hierarchy scale, the quality of data use was lacking most for utilities. The quality of study design was scored as 82, 92, and 100 for each study using the Quality of Health Economic Studies instrument. CONCLUSIONS: Although a limited number of economic evaluations were identified, the studies evaluated here were well designed. The interventions assessed were all considered cost-effective, but pooled analysis was not possible because of heterogeneity in the interventions assessed. Given the importance of value and cost-effectiveness in medical care, more evidence is needed in this area.

The economic impact of glioma survivorship: The cost of care from a patient perspective.

OBJECTIVE: We aimed to characterize the socioeconomic impact of glioma for patients with clinical and radiographic evidence of disease stability, using the standardized Medical Expenditure Panel Survey-Household Component (MEPS-HC). METHODS: The MEPS-HC questionnaire was used to investigate the degree of economic hardship referable to the patient's brain tumor and treatment. The questionnaire included demographic variables such as age at diagnosis, ethnicity, highest level of education, and annual household income. Descriptive statistics were used to characterize variables and between-group comparisons were evaluated using Fisher exact test. RESULTS: Of 127 prescreened patients, 89 of 107 eligible patients completed the survey. Pathology at diagnosis was predominantly low grade (60%). Most patients were insured at time of diagnosis (91%), married (76%), and employed (79%), with annual household incomes slightly higher than the national average. Despite this, nearly a quarter incurred debt referable to brain tumor care (24%), 53% required extended unpaid time off, and 46% retired or were no longer working. Financial burden and workforce morbidity were insensitive to tumor location, laterality, and annual household income. Patients with gross total resection at initial surgery were less likely to report ongoing limitations in daily activities (45% vs 83%, p = 0.004). CONCLUSIONS: Even in a population of stable, high-functioning glioma survivors, financial burden and workforce morbidity was ubiquitous across all tumor subtypes, treatment paradigms, and income levels.

Genomic Biomarker Assessment in Gliomas: Impacts of Molecular Testing on Clinical Practice and Trial Design.

Recent discoveries elucidating the genetic underpinnings of glial neoplasms have revealed myriad recurrent alterations that have clinical value by improving accuracy of diagnosis and prognosis. Furthermore, this wealth of genomic information provides the basis for targeted therapies and the subsequent design of biomarker-based clinical trials. This review summarizes the current landscape of clinically relevant molecular alterations in gliomas and describes the role of routine molecular testing in context of treatment planning for standards of care and clinical trials.

Healthcare utilization and productivity loss in glioma patients and family caregivers: the impact of treatable psychological symptoms.

BACKGROUND: Gliomas are associated with significant healthcare burden, yet reports of costs are scarce. While many costs are unavoidable there may be treatable symptoms contributing to higher costs. We describe healthcare and societal costs in glioma patients at high risk for depression and their family caregivers, and explore relationships between costs and treatable symptoms. METHODS: Data from a multicenter randomized trial on effects of internet-based therapy for depressive symptoms were used (NTR3223). Costs of self-reported healthcare utilization, medication use, and productivity loss were calculated for patients and caregivers separately. We used generalized linear regression models to predict costs with depressive symptoms, fatigue, cognitive complaints, tumor grade (low-/high-grade), disease status (stable or active/progression), and intervention (use/non-use) as predictors. RESULTS: Multiple assessments from baseline through 12 months from 91 glioma patients and 46 caregivers were used. Mean overall costs per year were M = €20,587.53 (sd = €30,910.53) for patients and M = €5,581.49 (sd = €13,102.82) for caregivers. In patients, higher healthcare utilization costs were associated with more depressive symptoms; higher medication costs were associated with active/progressive disease. In caregivers, higher overall costs were linked with increased caregiver fatigue, cognitive complaints, and lower patient tumor grade. Higher healthcare utilization costs were related to more cognitive complaints and lower tumor grade. More productivity loss costs were associated with increased fatigue (all P < 0.05). CONCLUSIONS: There are substantial healthcare and societal costs for glioma patients and caregivers. Associations between costs and treatable psychological symptoms indicate that possibly, adequate support could decrease costs. TRIAL REGISTRATION: Netherlands Trial Register NTR3223.

Costs and Complications Associated With Resection of Supratentorial Tumors With and Without the Operative Microscope in the United States.

BACKGROUND: The operative microscope, a commonly used tool in neurosurgery, is critical in many supratentorial tumor cases. However, use of operating microscope for supratentorial tumor varies by surgeon. OBJECTIVES: To assess complication rates, readmissions, and costs associated with operative microscope use in supratentorial resections. METHODS: A retrospective analysis was conducted using a national administrative database to identify patients with glioma or brain metastases who underwent supratentorial resection between 2007 and 2016. Univariate and multivariate analyses were used to assess 30-day complications, readmissions, and costs between patients who underwent resection with and without use of microscope. RESULTS: The cohort included 12,058 glioma patients and 5433 metastasis patients. Rates of microscope use varied by state from 19.0% to 68.6%. Microscope use was associated with $5228.90 in additional costs of index hospitalization among glioma patients (P <0.001), and $2824.00 among metastasis patients (P <0.001). Rates of intraoperative cerebral edema were lower among the microscope cohort than among the nonmicroscope cohort (P <0.027). Microscope use was associated with a slight reduction in 30-day rates of neurological complications (14.7% vs. 16.7%, P = 0.048), specifically in nonspecific cerebrovascular complications. There were no differences in rates of other complications, readmissions, or 30-day postoperative costs. CONCLUSIONS: Use of operative microscope for supratentorial resections varies by state and is associated with higher cost of surgery. Microscope use may be associated with lower rates of intraoperative cerebral edema and some cerebrovascular complications, but is not associated with significant differences in other complications, readmissions, or 30-day costs.

Socioeconomic factors affect treatment delivery for patients with low grade glioma: a Swedish population-based study.

BACKGROUND: Despite aspirations to achieve equality in healthcare we know that socioeconomic differences exist and may affect treatment and patient outcome, also in serious diseases such as cancer. We investigated disparities in neurosurgical care and outcome for patients with low-grade glioma (LGG). METHODS: In this nationwide registry-based study, patients who had undergone surgery for LGG during 2005-2015 were identified (n = 547) through the Swedish Brain Tumor Registry. We linked data to multiple national registries with individual level data on income, education and comorbidity and analyzed the association of disease characteristics, surgical management and outcome, with levels of income, education and sex. RESULTS: Patients with either low income, low education or female gender showed worse pre-operative performance status. Patients with low income or education also had more comorbidities and those with low education endured longer waiting times for surgery. Median time from radiological imaging to surgery was 51 days (Q1-3 27-191) for patients with low education, compared to 32 days (Q1-3 20-80) for patients with high education (p = 0.006). Differences in waiting time over educational levels remained significant after stratification for age, comorbidity, preoperative performance status, and tumor size. Overall survival was better for patients with high income or high education, but income- and education-related survival differences were not significant after adjustment for age and comorbidity. The type of surgical procedure or complications did not differ over socioeconomic groups or sex. CONCLUSION: The neurosurgical care for LGG in Sweden, a society with universal healthcare, displays differences that can be related to socioeconomic factors.

Quality-adjusted life years in glioma patients: a systematic review on currently available data and the lack of evidence-based utilities.

BACKGROUND: Cost-effectiveness studies gain importance in the context of rising health care expenses and treatment options. Especially in the neuro-oncological context, surgical therapy may increase overall survival, but restrain the patient by postoperative disability. Quality-adjusted life years, express treatment effects and are based on health utilities. In our study, we analyze the current evidence on health economic evaluations in glioma patients. MATERIAL AND METHODS: We performed a systematic database search including Medline and Cochrane Library. Studies were critically appraised for statistical analyzes including glioma patients, health economic modeling and detailed health outcome. Study evidence was classified according to levels of evidence for therapeutic studies from the Centre for Evidence-Based Medicine (Oxford). RESULTS: 37 studies (1995-2018) were identified, 29 matched our inclusion criteria. Studies addressed surgical cost-efficiency and/or the standard treatment, postoperative chemotherapy (n = 6) and 5-ALA (n = 3). Only 16 studies used QALY as the outcome measure, most used overall survival or life years gained (LYG). Utilities were either based on one single study (Garside et al. in Health Technol Assess 11:iii-iv, ix-221) or derived from visual analogue scale (VAS). None assessed quality of life values for specific health statuses or utilities. Incremental cost-effectiveness ratios varied from 8325€ per QALY (5-ALA) to 518,342€ per LYG (tumor treating fields). CONCLUSIONS: Only one study generated utility values to conduct cost-effectiveness analysis (CEA); most studies used indirect outcomes such as LYG or based their model on previously published data. Health economic evaluations lack specific utilities, further investigations are necessary to conduct reliable CEA in the neurosurgical context.

Healthcare Costs for High-grade Glioma.

BACKGROUND/AIM: Data on verified healthcare costs for high-grade gliomas (HGGs) are limited. This study aimed to determine the healthcare costs for HGGs. MATERIALS AND METHODS: A total of 88 primary HGGs patients diagnosed and treated at our Institution between 2011 and 2017 who had insurance plans administered with Excellus BCBS were retrospectively identified. Patient clinical information was linked with all verified insurance payment data. RESULTS: Median insurance payments for clinical management of HGGs were $184,159.83. The leading cost was therapeutic radiation oncology. Patients under commercial insurance had a longer survival time, and higher healthcare expenditures in total and in each phase of clinical care. Healthcare costs were higher during therapy initiation and at disease recurrence and lower during the interim. A generalized linear model showed that patients with commercial insurance, better Karnofsky Performance Status, and longer survival time had higher healthcare expenditures. CONCLUSION: Healthcare payments for HGGs patients were substantial and such high healthcare expenditures were positively associated with patient survival and commercial insurance.

Cost-effectiveness of Intraoperative MRI for Treatment of High-Grade Gliomas.

Background Intraoperative MRI has been shown to improve gross-total resection of high-grade glioma. However, to the knowledge of the authors, the cost-effectiveness of intraoperative MRI has not been established. Purpose To construct a clinical decision analysis model for assessing intraoperative MRI in the treatment of high-grade glioma. Materials and Methods An integrated five-state microsimulation model was constructed to follow patients with high-grade glioma. One-hundred-thousand patients treated with intraoperative MRI were compared with 100 000 patients who were treated without intraoperative MRI from initial resection and debulking until death (median age at initial resection, 55 years). After the operation and treatment of complications, patients existed in one of three health states: progression-free survival (PFS), progressive disease, or dead. Patients with recurrence were offered up to two repeated resections. PFS, valuation of health states (utility values), probabilities, and costs were obtained from randomized controlled trials whenever possible. Otherwise, national databases, registries, and nonrandomized trials were used. Uncertainty in model inputs was assessed by using deterministic and probabilistic sensitivity analyses. A health care perspective was used for this analysis. A willingness-to-pay threshold of $100 000 per quality-adjusted life year (QALY) gained was used to determine cost efficacy. Results Intraoperative MRI yielded an incremental benefit of 0.18 QALYs (1.34 QALYs with intraoperative MRI vs 1.16 QALYs without) at an incremental cost of $13 447 ($176 460 with intraoperative MRI vs $163 013 without) in microsimulation modeling, resulting in an incremental cost-effectiveness ratio of $76 442 per QALY. Because of parameter distributions, probabilistic sensitivity analysis demonstrated that intraoperative MRI had a 99.5% chance of cost-effectiveness at a willingness-to-pay threshold of $100 000 per QALY. Conclusion Intraoperative MRI is likely to be a cost-effective modality in the treatment of high-grade glioma. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Bettmann in this issue.

Financially effective test algorithm to identify an aggressive, EGFR-amplified variant of IDH-wildtype, lower-grade diffuse glioma.

BACKGROUND: Update 3 of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recognizes amplification of epidermal growth factor receptor (EGFR) as one important aberration in diffuse gliomas (World Health Organization [WHO] grade II/III). While these recommendations endorse testing, a cost-effective, clinically relevant testing paradigm is currently lacking. Here, we use real-world clinical data to propose a financially effective diagnostic test algorithm in the context of new guidelines. METHODS: To determine the prevalence, distribution, neuroradiographic features (Visually Accessible REMBRANDT Images [VASARI]), and prognostic relevance of EGFR amplification in lower-grade gliomas, we assembled a consecutive series of diffuse gliomas. For validation we included publicly available data from The Cancer Genome Atlas. For a cost-utility analysis we compared combined EGFR and isocitrate dehydrogenase (IDH) testing, EGFR testing based on IDH results, and no EGFR testing. RESULTS: In n = 71 WHO grade II/III gliomas, we identified EGFR amplification in 28.2%. With one exception, all EGFR amplifications occurred in IDH-wildtype gliomas. Comparison of overall survival showed that EGFR amplification denotes a significantly more aggressive subset of tumors (P < 0.0001, log-rank). The radiologic phenotype in the EGFR-amplified tumors includes diffusion restriction (15%, P = 0.02), >5% tumor contrast enhancement (75%, P = 0.016), and mild (not avid) enhancement (P = 0.016). The proposed testing algorithm reserves EGFR fluorescence in situ hybridization (FISH) testing for IDH-wildtype cases. Implementation would result in ~37.9% cost reduction at our institution, or about $1.3-4 million nationally. CONCLUSION: EGFR-amplified diffuse gliomas are "glioblastoma-like" in their behavior and may represent undersampled glioblastomas, or subsets of IDH-wildtype diffuse gliomas with inherently aggressive biology. EGFR FISH after IDH testing is a financially effective and clinically relevant test algorithm for routine clinical practice.

Analysis of Legal, Cultural, and Socioeconomic Parameters in Low-Grade Glioma Management: Variability Across Countries and Implications for Awake Surgery.

Low-grade glioma (LGG) usually occurs in young patients who enjoy an active family, social, and professional life. Because awake surgery for patients with LGG has resulted in significant improvement in both functional and oncological outcomes and because the surgery per se is not very expensive, it is currently performed in many countries worldwide. Nonetheless, in addition to the necessity of tailoring the surgical strategy to the patient (e.g., neurological and cognitive status) and tumor (e.g., brain location and volume) characteristics, the legal, cultural, and socioeconomic parameters could also play a key role in the therapeutic strategy. These include clear information to the patient and relatives during the first meeting, the adapted selection of tasks for awake mapping, and active collaboration of the patient throughout the resection and during the early postoperative rehabilitation. In the present study, our goal was to analyze these socioenvironmental aspects, which have been neglected for many decades, in LGG management, with a special emphasis on epilepsy and the awake procedure. These criteria are relevant with respect to the diagnosis, surgery, functional remediation, and long-term follow-up for patients who now benefit from a longer life expectancy. However, although such factors are essential to resume an active life, including returning to work, they vary greatly across countries. Therefore, they should be considered more systematically to allow for greater reproducibility of results of awake surgery worldwide.

Cost-effectiveness of preoperative motor mapping with navigated transcranial magnetic brain stimulation in patients with high-grade glioma.

OBJECTIVE Navigated transcranial magnetic stimulation (nTMS) is used to identify the motor cortex prior to surgery. Yet, there has, until now, been no published evidence on the economic impact of nTMS. This study aims to analyze the cost-effectiveness of nTMS, evaluating the incremental costs of nTMS motor mapping per additional quality-adjusted life year (QALY). By doing so, this study also provides a model allowing for future analysis of general cost-effectiveness of new neuro-oncological treatment options. METHODS The authors used a microsimulation model based on their cohort population sampled for 1000 patients over the time horizon of 2 years. A health care provider perspective was used to assemble direct costs of total treatment. Transition probabilities and health utilities were based on published literature. Effects were stated in QALYs and established for health state subgroups. RESULTS In all scenarios, preoperative mapping was considered cost-effective with a willingness-to-pay threshold < 3*per capita GDP (gross domestic product). The incremental cost-effectiveness ratio (ICER) of nTMS versus no nTMS was 45,086 Euros/QALY. Sensitivity analyses showed robust results with a high impact of total treatment costs and utility of progression-free survival. Comparing the incremental costs caused by nTMS implementation only, the ICER decreased to 1967 Euros/QALY. CONCLUSIONS Motor mapping prior to surgery provides a cost-effective tool to improve the clinical outcome and overall survival of high-grade glioma patients in a resource-limited setting. Moreover, the model used in this study can be used in the future to analyze new treatment options in neuro-oncology in terms of their general cost-effectiveness.

Shadow study: randomized comparison of clinic with video follow-up in glioma undergoing adjuvant temozolomide therapy.

AIM: This study was designed with a primary objective to study the rate of agreement in treatment plan and decisions between video follow-up (VF) and conventional clinic follow-up (CF). PATIENTS & METHODS: Adult patients with intermediate- to high-grade glioma on adjuvant temozolomide (TMZ) with facilities for live video call were invited to participate in the study. RESULTS: The concurrence in decision of administering TMZ between VF and CF was 100% (p < 0.00). The median cost incurred in VF was US$58.15 while that incurred in CF was US$131.23 (p < 0.00). CONCLUSION: VF can substitute CF during adjuvant TMZ administration (CTRI/2017/01/007626).

The role of income in brain tumor patients: a descriptive register-based study : No correlation between patients' income and development of brain cancer.

Socioeconomic status (SES) and its association with cancer in general have been thoroughly studied in the last decades. Several studies have shown associations between SES and many types of cancer such as lung cancer, breast cancer, and prostate cancer. For gliomas, no clear occupational or exposure risk factors have been identified, although some possible risk factors such as use of cellular telephone are still controversial. The aim in the present study is to analyze whether there is an association between SES and development of brain cancer. Data from 1999 through 2013 were collected from the Swedish Cancer Registry and from the National Statistics of Sweden. Age-standardized incidence rates for people with different income were calculated using linear regression model. A total of 11,892 patients were included, of which 5675 were meningiomas, 1216 low-grade gliomas, and 5001 high-grade gliomas. No clear trend between increasing incidence rates and higher income was seen in neither of the investigated brain tumor histologies. In conclusion, the results should be interpreted with caution, but there does not seem to be a correlation in this material between increased income and development of brain cancer.

Cost-effectiveness of IDH testing in diffuse gliomas according to the 2016 WHO classification of tumors of the central nervous system recommendations.

BACKGROUND: Due to the decreasing prevalence of IDH1 mutations in older patients, the 2016 World Health Organization (WHO) classification of brain tumors proposed not to perform sequencing for isocitrate dehydrogenase (IDH) in glioblastoma patients ≥55 years old. We present a cost-effectiveness analysis to estimate the financial impact of these guidelines. METHODS: From 2010 to 2015 we performed 1023 IDH tests in gliomas, amounting to ~$1.09 million in direct laboratory test costs. Samples were tested using R132H-specific immunohistochemistry, DNA sequencing validated for detection of noncanonical IDH1/2 mutations, or both methods. RESULTS: In cases tested by DNA sequencing, the fraction of non-R132H mutations was 5.4%, which included only 2 high-grade gliomas in patients ≥55 years (0.9%). When remodeling the optimal age cutoff in our patient population using 5-year age-binning, we found a 10-times higher pretest probability for the presence of a noncanonical IDH1 mutation in the setting of a negative IDH1-R132H immunohistochemistry result in patients <55 years. Applying the independently confirmed age cutoff of 55 years to glioblastoma patients (64%) would result in $403200 saved (43%). By not performing sequencing in patients ≥55 years, the turn-around time to final integrated neuropathological diagnosis is reduced by 53%, allowing these patients to gain earlier benefits from personalized genomic medicine. CONCLUSION: The negligible prevalence of noncanonical IDH mutations in glioblastoma patients ≥55 years argues against universal IDH sequencing in this population. We predict that adoption of this age-based sequencing cutoff recommendation from the 2016 WHO guidelines will result in significant cost and time savings throughout the global health care system.

Direct medical costs of treatment in newly-diagnosed high-grade glioma among commercially insured US patients.

AIM: This analysis assessed the direct medical costs of newly-diagnosed, temozolomide (TMZ)-treated glioblastoma (GBM) from the perspective of a US commercial setting. MATERIALS AND METHODS: The analysis included subjects identified from the IMS PharMetrics LifeLink Plus™ claims database from January 1, 2008 to August 31, 2014 who were ≥18 years of age, had ≥1 malignant brain cancer diagnosis, had brain surgery ≤90 days prior to TMZ initiation, had TMZ treatment, and were continuously enrolled for ≥12 months pre-diagnosis and ≥1 month post-diagnosis. Per-patient per-month (PPPM) and cumulative costs from 3 months pre-diagnosis to various post-diagnosis follow-up time points were calculated. Multivariable analyses were used to estimate adjusted mean cost and identify contributors of cost. RESULTS: The study included 2,921 subjects (median age = 56 years; 60% male). After diagnosis, the median (interquartile range, IQR) number of inpatient, emergency department, and outpatient visits were 2 (1-4), 1 (1-3), and 19 (13-27); median (IQR) length of stay per hospitalization was 5 (3-9) days. Mean total cumulative costs per patient from 3 months pre-diagnosis to 12 months and to 5 years post-diagnosis were $201,749 (197,490-206,024) and $268,031 (262,877-274,416). Mean (SD) PPPM costs were $818 (1,128) and $7,394 (8,676) pre- and post-GBM diagnosis, respectively. The variables most predictive of cumulative costs included radiation therapy (+$81,732), ≥2 weeks of hospitalization (+$49,629), and ≥7 MRI scans (+$40,105). CONCLUSIONS: The direct medical costs of newly-diagnosed, TMZ-treated GBM in commercially insured patients are substantial, with estimated total cumulative costs of $268,031.

Cost-effectiveness of radiation and chemotherapy for high-risk low-grade glioma.

BACKGROUND: The addition of procarbazine, lomustine, vincristine (PCV) chemotherapy to radiotherapy (RT) for patients with high-risk (≥40 y old or subtotally resected) low-grade glioma (LGG) results in an absolute median survival benefit of over 5 years. We evaluated the cost-effectiveness of this treatment strategy. METHODS: A decision tree with an integrated 3-state Markov model was created to follow patients with high-risk LGG after surgery treated with RT versus RT+PCV. Patients existed in one of 3 health states: stable, progressive, or dead. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Analysis was conducted from the health care perspective. Deterministic and probabilistic sensitivity analysis explored uncertainty in model parameters. RESULTS: Modeled outcomes demonstrated agreement with clinical data in expected benefit of addition of PCV to RT. The addition of PCV to RT yielded an incremental benefit of 4.77 quality-adjusted life-years (QALYs) (9.94 for RT+PCV vs 5.17 for RT alone) at an incremental cost of $48635 ($188234 for RT+PCV vs $139598 for RT alone), resulting in an incremental cost-effectiveness ratio of $10186 per QALY gained. Probabilistic sensitivity analysis demonstrates that within modeled distributions of parameters, RT+PCV has 99.96% probability of being cost-effectiveness at a willingness-to-pay threshold of $100000 per QALY. CONCLUSION: The addition of PCV to RT is a cost-effective treatment strategy for patients with high-risk LGG.

The effectiveness and cost-effectiveness of intraoperative imaging in high-grade glioma resection; a comparative review of intraoperative ALA, fluorescein, ultrasound and MRI.

BACKGROUND: Surgical resection of high-grade gliomas (HGG) is standard therapy because it imparts significant progression free (PFS) and overall survival (OS). However, HGG-tumor margins are indistinguishable from normal brain during surgery. Hence intraoperative technology such as fluorescence (ALA, fluorescein) and intraoperative ultrasound (IoUS) and MRI (IoMRI) has been deployed. This study compares the effectiveness and cost-effectiveness of these technologies. METHODS: Critical literature review and meta-analyses, using MEDLINE/PubMed service. The list of references in each article was double-checked for any missing references. We included all studies that reported the use of ALA, fluorescein (FLCN), IoUS or IoMRI to guide HGG-surgery. The meta-analyses were conducted according to statistical heterogeneity between studies. If there was no heterogeneity, fixed effects model was used; otherwise, a random effects model was used. Statistical heterogeneity was explored by χ2 and inconsistency (I2) statistics. To assess cost-effectiveness, we calculated the incremental cost per quality-adjusted life-year (QALY). RESULTS: Gross total resection (GTR) after ALA, FLCN, IoUS and IoMRI was 69.1%, 84.4%, 73.4% and 70% respectively. The differences were not statistically significant. All four techniques led to significant prolongation of PFS and tended to prolong OS. However none of these technologies led to significant prolongation of OS compared to controls. The cost/QALY was $16,218, $3181, $6049 and $32,954 for ALA, FLCN, IoUS and IoMRI respectively. CONCLUSIONS: ALA, FLCN, IoUS and IoMRI significantly improve GTR and PFS of HGG. Their incremental cost was below the threshold for cost-effectiveness of HGG-therapy, denoting that each intraoperative technology was cost-effective on its own.

A pilot cost-effectiveness analysis of treatments in newly diagnosed high-grade gliomas: the example of 5-aminolevulinic Acid compared with white-light surgery.

BACKGROUND: High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). OBJECTIVE: To evaluate the cost-effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. METHODS: We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life-years, life-years, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratios are below &OV0556;10 000 in all evaluated outcomes, being around &OV0556;9100 per quality-adjusted life-year gained, &OV0556;6700 per life-year gained, and &OV0556;8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of &OV0556;20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. CONCLUSION: 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high-grade gliomas compared with white-light surgery. This example demonstrates cost-effectiveness analyses for malignant glioma surgery to be feasible on the basis of existing data.

Economics of Malignant Gliomas: A Critical Review.

PURPOSE: Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society. METHODS: A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another. RESULTS: Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial. CONCLUSION: With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-of-pocket and total medical costs continue to evolve. Larger out-of-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively.