Multi-modal management of acromegaly: a value perspective.

PURPOSE: The Acromegaly Consensus Group recently released updated guidelines for medical management of acromegaly patients. We subjected these guidelines to a cost analysis. METHODS: We conducted a cost analysis of the recommendations based on published efficacy rates as well as publicly available cost data. The results were compared to findings from a previously reported comparative effectiveness analysis of acromegaly treatments. Using decision tree software, two models were created based on the Acromegaly Consensus Group's recommendations and the comparative effectiveness analysis. The decision tree for the Consensus Group's recommendations was subjected to multi-way tornado analysis to identify variables that most impacted the value analysis of the decision tree. RESULTS: The value analysis confirmed the Consensus Group's recommendations of somatostatin analogs as first line therapy for medical management. Our model also demonstrated significant value in using dopamine agonist agents as upfront therapy as well. Sensitivity analysis identified the cost of somatostatin analogs and growth hormone receptor antagonists as having the most significant impact on the cost effectiveness of medical therapies. CONCLUSION: Our analysis confirmed the value of surgery as first-line therapy for patients with surgically accessible lesions. Surgery provides the greatest value for management of patients with acromegaly. However, in accordance with the Acromegaly Consensus Group's recent recommendations, somatostatin analogs provide the greatest value and should be used as first-line therapy for patients who cannot be managed surgically. At present, the substantial cost is the most significant negative factor in the value of medical therapies for acromegaly.

Bevacizumab for radiation necrosis following treatment of high grade glioma: a systematic review of the literature.

This review identifies the current literature on the use of bevacizumab for cerebral radiation necrosis in patients with high-grade gliomas, summarizes the clinical course and complications following bevacizumab, and discusses the relative costs and benefits of this therapeutic option. A Medline search was conducted of all clinical studies before September 2012 investigating outcomes following use of bevacizumab therapy for radiation necrosis in patients with high-grade gliomas. Clinical and radiographic outcomes are reviewed. Seven studies reported a total of 30 patients with high-grade gliomas treated with bevacizumab for radiation necrosis. All patients demonstrated decreased radiographic volume of edema on T1 and T2 MRI sequences. Clinical outcomes were reported for 23 patients: 16 (70 %) had improvement in neurologic signs or symptoms, 5 (22 %) had mixed results, and 2 (9 %) remained neurologically unchanged. Complications were documented in 5 of 7 studies (18 of 29 patients, 62 %) and included deep vein thrombosis, pulmonary embolism, visual field worsening, worsening hemiplegia, pneumonia, seizure, and fatigue. Only one study evaluated quality of life measures and none evaluated cost or cost effectiveness. Data regarding the use of bevacizumab to treat radiation necrosis in patients with high-grade gliomas is limited and primarily class III evidence. While bevacizumab improves neurological symptoms and reduces radiographic volume of necrosis-associated cerebral edema, it comes at the expense of a high rate of potentially serious complications. Definitive evidence for the utility, cost-effectiveness, and overall efficacy of this management strategy is currently lacking and additional investigation is warranted.

The molecular biology of WHO grade II gliomas.

The WHO grading scheme for glial neoplasms assigns Grade II to 5 distinct tumors of astrocytic or oligodendroglial lineage: diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, pleomorphic xanthoastrocytoma, and pilomyxoid astrocytoma. Although commonly referred to collectively as among the "low-grade gliomas," these 5 tumors represent molecularly and clinically unique entities. Each is the subject of active basic research aimed at developing a more complete understanding of its molecular biology, and the pace of such research continues to accelerate. Additionally, because managing and predicting the course of these tumors has historically proven challenging, translational research regarding Grade II gliomas continues in the hopes of identifying novel molecular features that can better inform diagnostic, prognostic, and therapeutic strategies. Unfortunately, the basic and translational literature regarding the molecular biology of WHO Grade II gliomas remains nebulous. The authors' goal for this review was to present a comprehensive discussion of current knowledge regarding the molecular characteristics of these 5 WHO Grade II tumors on the chromosomal, genomic, and epigenomic levels. Additionally, they discuss the emerging evidence suggesting molecular differences between adult and pediatric Grade II gliomas. Finally, they present an overview of current strategies for using molecular data to classify low-grade gliomas into clinically relevant categories based on tumor biology.

Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial.

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.

Predicting survival in women with breast cancer and brain metastasis: a nomogram outperforms current survival prediction models.

BACKGROUND: Brain metastases (BMs) are a common occurrence in patients with breast cancer, and accurately predicting survival in these patients is critical to appropriate management. A survival nomogram for breast cancer patients with BM was constructed, and its performance is compared to current predictive models of survival. METHODS: A Cox proportional hazards regression with a nomogram representation was used to model survival in a population of 261 women with breast cancer and BMs treated from 1999 to 2008. The model was validated internally by 10-fold cross-validation and bootstrapping, and concordance (c) indices were calculated. The predictive performance of the nomogram described here is compared to current prognostic models, including recursive partitioning analysis, graded prognostic assessment, and diagnosis-specific graded prognostic assessment. RESULTS: The c-index for the model described here was 0.67. It outperformed recursive partitioning analysis, graded prognostic assessment, and diagnosis-specific graded prognostic assessment, based on c-index comparisons. CONCLUSIONS: The nomogram described here outperformed current strategies for survival prediction in breast cancer patients with BMs. Two additional advantages of this nomogram are its ability to predict individualized, 1-, 3-, and 5-year survival for novel patients and its straightforward representations of the relative effects of each of 9 covariates on neurologic survival. This represents a potentially valuable alternative to current models of survival prediction in this patient population.

Impact of preexisting tumor necrosis on the efficacy of stereotactic radiosurgery in the treatment of brain metastases in women with breast cancer.

BACKGROUND: Breast cancer is the second most common source of brain metastasis. Stereotactic radiosurgery (SRS) can be an effective treatment for some patients with brain metastasis (BM). Necrosis is a common feature of many brain tumors, including BM; however, the influence of tumor necrosis on treatment efficacy of SRS in women with breast cancer metastatic to the brain is unknown. METHODS: A cohort of 147 women with breast cancer and BM treated consecutively with SRS over 10 years were studied. Of these, 80 (54.4%) had necrosis identified on pretreatment magnetic resonance images and 67 (46.4%) did not. Survival times were computed using the Kaplan-Meier method. Log-rank tests were used to compare groups with respect to survival times, Cox proportional hazards regression models were used to perform univariate and multivariate analyses, and chi-square and Fisher exact tests were used to compare clinicopathologic covariates. RESULTS: Neurological survival (NS) and survival after SRS were decreased in BM patients with necrosis at the time of SRS compared with patients without necrosis by 32% and 27%, respectively (NS median survival, 25 vs 17 months [log-rank test, P = .006]; SRS median survival, 15 vs 11 months [log-rank test, P = .045]). On multivariate analysis, HER2 amplification status and necrosis influenced NS and SRS after adjusting for standard clinical features, including BM number, size, and volume as well as Karnofsky performance status. CONCLUSION: Neuroimaging evidence of necrosis at the time of SRS significantly diminished the efficacy of therapy and was a potent prognostic marker.

Hypertonic saline, not mannitol, should be considered gold-standard medical therapy for intracranial hypertension.

Hyperosmolar therapy is the principal medical management strategy for elevated intracranial pressure. Mannitol has been the primary hyperosmolar agent for nearly a century and remains the de facto gold standard for medical management of intracranial hypertension. Over the past 25 years, however, hypertonic saline (HTS) has become a progressively more common alternative to mannitol, and several recent studies have suggested its relative superiority. These findings have prompted calls for large-scale comparator trials of mannitol and HTS, but such trials would only be necessary if the designation of mannitol as the gold standard is appropriate and if current evidence suggests its therapeutic equipoise with HTS. Mounting evidence supporting HTS suggests that neither of these conditions is necessarily true and, instead, mandates reassessment of the actual gold-standard agent for hyperosmolar therapy. In the present article I make the case that current evidence supports HTS, not mannitol, as the better choice for gold-standard therapy for medical management of intracranial hypertension. This is accomplished first by examining the evidence on which the apparent designation of mannitol as the presumed gold-standard is based, then by reviewing the recent comparative efficacy data for HTS versus mannitol, and finally by discussing additional clinical considerations for appropriate designation of a gold-standard agent for hyperosmolar therapy. This assessment has important implications both for patient care and for clinical trial design.

The case for a comparative, value-based alternative to the patient-centered outcomes research model for comparative effectiveness research.

Considerable financial and human resources have been directed toward the emerging field of comparative effectiveness research (CER) in the US. Fundamentally, the concept of CER is so logical as to be almost self-evident; namely, that research regarding therapeutic strategies should go beyond efficacy and examine objectively their real-world effects and outcomes. In practice, however, reluctance to consider difficult questions related to the many dimensions of value in health care delivery and corresponding legislative constraints placed on the US CER enterprise risk limiting the ultimate utility of this investigative model. Significant constraints have been codified into the patient-centered outcomes research (PCOR) model of CER, which is emerging as the de facto method for conducting CER in the US. The experience of the authors as clinicians attempting to use CER to improve complex management decisions, for which multidimensional considerations of value represent a critical component of the overall effectiveness of alternate strategies, highlight the inability of PCOR to comprehensively inform this process. This suggests that PCOR may be a suboptimal approach for performing clinically relevant CER. In this editorial, the authors use clinical examples to highlight the limitations of the PCOR approach to CER and to propose an alternate approach, which they term "comparative, value-based effectiveness research" (CVER). The authors believe that the narrow scope and fundamental limitations of PCOR mitigate its overall value to medical decision-makers attempting to optimize overall effectiveness in the real-world setting, while a more comprehensive approach like CVER has greater potential to realize practical benefits for patients, clinicians, and society as a whole.

Hyperosmolar therapy for intracranial hypertension.

The use of hyperosmolar agents for intracranial hypertension was introduced in the early 20th century and remains a mainstay of therapy for patients with cerebral edema. Both animal and human studies have demonstrated the efficacy of two hyperosmolar agents, mannitol and hypertonic saline, in reducing intracranial pressure via volume redistribution, plasma expansion, rheologic modifications, and anti-inflammatory effects. However, because of physician and institutional variation in therapeutic practices, lack of standardized protocols for initiation and administration of therapy, patient heterogeneity, and a paucity of randomized controlled trials have yielded little class I evidence on which clinical decisions can be based, most current evidence regarding the use of hyperosmolar therapy is derived from retrospective analyses (class III) and case series (class IV). In this review, we summarize the available evidence regarding the use of hyperosmolar therapy with mannitol or hypertonic saline for the medical management of intracranial hypertension and present a comprehensive discussion of the evidence associated with various theoretical and practical concerns related to initiation, dosage, and monitoring of therapy.

Integrin α3ß1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis.

Therapeutic targeting of angiogenesis in glioblastoma has yielded mixed outcomes. Investigation of tumor-associated angiogenesis has focused on the factors that stimulate the sprouting, migration, and hyperproliferation of the endothelial cells. However, little is known regarding the processes underlying the formation of the tumor-associated vessels. To address this issue, we investigated vessel formation in CD31+ cells isolated from human glioblastoma tumors. The results indicate that overexpression of integrin α3ß1 plays a central role in the promotion of tube formation in the tumor-associated endothelial cells in glioblastoma. Blocking α3ß1 function reduced sprout and tube formation in the tumor-associated endothelial cells and vessel density in organotypic cultures of glioblastoma. The data further suggest a mechanistic model in which integrin α3ß1-promoted calcium influx stimulates macropinocytosis and directed maturation of the macropinosomes in a manner that promotes lysosomal exocytosis during nascent lumen formation. Altogether, our data indicate that integrin α3ß1 may be a therapeutic target on the glioblastoma vasculature.

Gamma knife stereotactic radiosurgery for the management of incidentally-identified brain metastasis from non-small cell lung cancer.

Initial staging workup of non-small cell lung cancer (NSCLC) patients has led to increased identification of incidental brain metastases in patients who otherwise have minimal or no neurologic symptoms. We present our experience treating these metastases with stereotactic radiosurgery (SRS) alone and compare outcomes to those of patients with brain metastases treated with other strategies. We queried our neuro-oncology and radiation oncology databases for patients with incidentally-identified NSCLC brain metastases treated with upfront SRS alone between 1997 and 2006. We performed a retrospective analysis to evaluate outcomes in these patients. We found 26 patients with incidentally-identified NSCLC brain metastases (KPS 90-100) treated with SRS alone within 60 days of diagnosis of the metastases. These patients underwent SRS at a median 15 days from diagnosis to an average of 1.6 lesions (range: 1-7), with a mean lesion volume of 1.86 cm(3). The median prescription was 24 Gy delivered to the median 53% isodose line. The median survival for these patients was 8.2 months (mean 12.3 months) from diagnosis of brain metastases. Local CNS progression occurred in 2 patients (7.7%, mean 229.7 days). Survival was not statistically different from similar patients treated with whole brain radiotherapy (WBRT) (P = 0.98), WBRT + Surgery (P = 0.07) or WBRT + SRS (P = 0.62). Patients with incidentally-identified NSCLC brain metastases treated with SRS alone may achieve a survival rate comparable to patients managed with other standard therapeutic modalities. Our findings suggest that SRS alone may be a viable therapeutic option for patients with incidentally-discovered NSCLC brain metastases.

Integrated molecular analysis suggests a three-class model for low-grade gliomas: a proof-of-concept study.

INTRODUCTION: We used an integrated molecular analysis strategy to perform class discovery on a population of low-grade gliomas (astrocytomas, oligodendrogliomas, and mixed gliomas) to improve our understanding of the molecular relationships among these tumors and to reconcile genotypic relationships with current histologic and molecular strategies for tumor classification. METHODS: Gene expression profiling was performed on a cross-section of World Health Organization (WHO) grades I-II gliomas. Unsupervised class discovery algorithms identified and validated tumor clusters with genotypic similarity, and these data were integrated with chromosomal copy number assays and RT-PCR data to define molecular tumor subclasses. Machine learning models allowed accurate, prospective classification of unknown tumors into these molecular subgroups. This molecular classification model was compared to current histologic (WHO) and molecular pathologic (chromosome 1p and 19q deletions, p53 alterations, and Ki-67 expression) methods for glioma classification. RESULTS: Molecular class discovery suggested a three-class model for low-grade gliomas. One discrete cluster of gliomas identified the pilocytic astrocytomas, a second grouped the 1p/19q codeleted oligodendrogliomas, and the mixture of remaining 1p/19q intact gliomas, including astrocytomas, oligodendrogliomas, and oligoastrocytomas, formed a third cluster with a discrete pattern of expression. CONCLUSIONS: Integration of genomic, transcriptomic, and morphologic data for class discovery suggests a three-class model for low-grade gliomas. Class I represents tumors with molecular similarity to pilocytic astrocytomas, class II tumors are similar to 1p/19q codeleted oligodendrogliomas, and class III represents infiltrative low-grade gliomas. This classification is similar to current clinical paradigms for low-grade gliomas; our work suggests a molecular basis for such models. This classification may supplement or may serve as the basis for a molecular pathologic alternative to current grading schemes for low-grade gliomas and may highlight potential targets for future biologically based treatments or strategies for future clinical trials.

The role of observational investigations in comparative effectiveness research.

INTRODUCTION: Comparative effectiveness research (CER) seeks to inform clinical decisions between alternate treatment strategies using data that reflects real patient populations and real-world clinical scenarios for the purpose of improving patient outcomes. There are multiple clinical situations where the unique characteristics of observational investigations can inform medical decision-making within the CER paradigm. Accordingly, it is critical for clinicians to appreciate the strengths and limitations of observational research, particularly as they apply to CER. METHODS: This review focuses on the role of observational research in CER. We discuss the concept of evidence hierarchies as they relate to observational research and CER, review the scope and nature of observational research, present the rationale for its inclusion in CER investigations, discuss potential sources of bias in observational investigations as well as strategies used to compensate for these biases, and discuss a framework to implement observational research in CER. CONCLUSIONS: The CER paradigm recognizes the limitations of hierarchical models of evidence and favors application of a strength-of-evidence model. In this model, observational research fills gaps in randomized clinical trial data and is particularly valuable to investigate effectiveness, harms, prognosis, and infrequent outcomes as well as in circumstances where randomization is not possible and in studies of many surgical populations. Observational investigations must be designed with careful consideration of potential sources of bias and must incorporate strategies to control such bias prospectively, and their results must be reported in a uniform and transparent fashion. When these conditions can be achieved, observational research represents a valuable and critical component of modern CER.

Immediate postoperative cortisol levels accurately predict postoperative hypothalamic-pituitary-adrenal axis function after transsphenoidal surgery for pituitary tumors.

Accurate assessment of the hypothalamic-pituitary-adrenal (HPA) axis is critical for the appropriate management of patients with pituitary adenoma after transsphenoidal surgery. We examine the role of immediate postoperative cortisol levels to assess hypothalamic-pituitary-adrenal axis (HPA) axis function post-operatively. We performed preoperative cortrosyn stimulation test (CST) and measured immediate postoperative serum cortisol levels in 100 patients undergoing 104 transsphenoidal surgeries. These results were compared to those of the CST at 4-6 weeks postoperatively, which served as a measure of HPA axis function. The ability of immediate postoperative, day of surgery (DOS) cortisol levels to predict normal HPA axis function was determined using standard predictive analytic methods and confusion matrix calculations. We found that postoperative, DOS cortisol level > or =15 microg/dL is a sensitive and accurate predictors of normal postoperative HPA axis function, with a sensitivity of 98%, an accuracy of 97%, and a positive predictive value of 99%. Our data suggest that an immediate, postoperative, DOS cortisol level > or =15 microg/dL predicts distant, normal, post-operative HPA axis function following transsphenoidal surgery.

Use of morning serum cortisol level after transsphenoidal resection of pituitary adenoma to predict the need for long-term glucocorticoid supplementation.

OBJECT: Accurate assessment of the hypothalamic-pituitary-adrenal (HPA) axis is critical for appropriate management of the disease in patients with pituitary adenoma after transsphenoidal resection. The authors examine the role of the morning total serum cortisol level in the early postoperative period as a predictor of long-term HPA function. METHODS: Morning total serum cortisol was measured in 83 patients on postoperative Day 1 (or Day 2 if the patient received glucocorticoids during surgery) after transsphenoidal surgery for pituitary adenoma. These results were compared with those of definitive assays of HPA function performed at 1-3 months postoperatively, including cortrosyn/synacthen stimulation test (CST), insulin tolerance test (ITT), and metyrapone test (MTT). The ability of the early-postoperative morning cortisol level to predict HPA function was determined using standard confusion matrix calculations and receiver-operator control curve analysis. RESULTS: The authors found that an early postoperative morning total cortisol level>or=15 microg/dl is a sensitive and accurate predictor of normal HPA function in the postoperative period (sensitivity 80.5%, specificity 66.7%, positive predictive value 96.9%). CONCLUSIONS: A morning total cortisol level>or=15 microg/dl in the early postoperative period after transsphenoidal surgery for pituitary adenomas is a good predictor of normal HPA function. This test has good sensitivity and accuracy and correlates well with the results of additional, definitive assays of HPA function (CST, ITT, and MTT) performed at 1-3 months postoperatively. Accordingly, it is the authors' practice to avoid exogenous perioperative glucocorticoid supplementation in patients with normal preoperative HPA function and postoperative morning total cortisol levels>or=15 microg/dl 1-2 days after transsphenoidal pituitary adenomectomy.

Genomic expression patterns distinguish long-term from short-term glioblastoma survivors: a preliminary feasibility study.

We used microarray analysis to investigate associations between genotypic expression profiles and survival phenotypes in patients with primary glioblastoma (GBM). Tumor samples from 7 long-term glioblastoma survivors (>24 months) and 13 short-term survivors (<9 months) were analyzed to detect differential patterns of gene expression between these groups and to identify genotypic subclasses of glioblastomas that correlate with survival phenotypes. Five unsupervised and three supervised clustering algorithms consistently and accurately grouped the tumors into genotypic subgroups corresponding to the two clinical survival phenotypes. Three unique prospective mathematical classification algorithms were subsequently trained to use expression data to stratify unknown glioblastomas between survival groups and performed this task with 100% accuracy in validation studies. A set of 1478 genes with significant differential expression (p<0.01) between long-term and short-term survivors was identified, and additional mathematical filtering was used to isolate a 43-gene "fingerprint" that distinguished survival phenotypes. Differential regulation of a subset of these genes was confirmed using RT-PCR. Gene ontology analysis of the fingerprint demonstrated pathophysiologic functions for the gene products that are consistent with current models of tumor biology, suggesting that differential expression of these genes may contribute etiologically to the observed differences in survival. These results demonstrate that unique expression profiles characterize genotypic subsets of primary GBMs associated with differential survival phenotypes, and these profiles can be used in a prospective fashion to assign unknown tumors to survival groups. Future efforts will focus on building more robust classifiers and identifying additional subclasses of gliomas with phenotypic significance.

From Clinical Trial Efficacy to Real-Life Effectiveness: Why Conventional Metrics do not Work.

BACKGROUND: Randomised, double-blind, clinical trial methodology minimises bias in the measurement of treatment efficacy. However, most phase III trials in non-orphan diseases do not include individuals from the population to whom efficacy findings will be applied in the real world. Thus, a translation process must be used to infer effectiveness for these populations. Current conventional translation processes are not formalised and do not have a clear theoretical or practical base. There is a growing need for accurate translation, both for public health considerations and for supporting the shift towards personalised medicine. OBJECTIVE: Our objective was to assess the results of translation of efficacy data to population efficacy from two simulated clinical trials for two drugs in three populations, using conventional methods. METHODS: We simulated three populations, two drugs with different efficacies and two trials with different sampling protocols. RESULTS: With few exceptions, current translation methods do not result in accurate population effectiveness predictions. The reason for this failure is the non-linearity of the translation method. One of the consequences of this inaccuracy is that pharmacoeconomic and postmarketing surveillance studies based on direct use of clinical trial efficacy metrics are flawed. CONCLUSION: There is a clear need to develop and validate functional and relevant translation approaches for the translation of clinical trial efficacy to the real-world setting.

Systematic Review of Safety and Cost-Effectiveness of Venous Thromboembolism Prophylaxis Strategies in Patients Undergoing Craniotomy for Brain Tumor.

BACKGROUND: Studies have evaluated various strategies to prevent venous thromboembolism (VTE) in neuro-oncology patients, without consensus. OBJECTIVE: To perform a systematic review with cost-effectiveness analysis (CEA) of various prophylaxis strategies in tumor patients undergoing craniotomy to determine the safest and most cost-effective prophylaxis regimen. METHODS: A literature search was conducted for VTE prophylaxis in brain tumor patients. Articles reporting the type of surgery, choice of VTE prophylaxis, and outcomes were included. Safety of prophylaxis strategies was determined by measuring rates of VTE and intracranial hemorrhage. Cost estimates were collected based on institutional data and existing literature. CEA was performed at 30 d after craniotomy, comparing the following strategies: mechanical prophylaxis (MP), low molecular weight heparin with MP (MP+LMWH), and unfractionated heparin with MP (MP+UFH) to prevent symptomatic VTE. All costs were reported in 2016 US dollars. RESULTS: A total of 34 studies were reviewed (8 studies evaluated LMWH, 12 for MP, and 7 for UFH individually or in combination; 4 studies used LMWH and UFH preoperatively). Overall probability of VTE was 1.49% (95% confidence interval (CI) 0.42-3.72) for MP+UFH, 2.72% [95% CI 1.23-5.15] for MP+LMWH, and 2.59% (95% CI 1.31-4.58) for MP, which were not statistically significant. Compared to a control of MP alone, the number needed to treat for MP+UFH is 91 and 769 for MP+LMWH. The risk of intracranial hemorrhage was 0.26% (95% CI 0.01-1.34) for MP, 0.74% (95% CI 0.09-2.61) for MP+UFH, and 2.72% (95% CI 1.23-5.15) for MP+LMWH, which were also not statistically significant. Compared to MP, the number needed to harm for MP+UFH was 208 and for MP+LMWH was 41. Fifteen studies were included in the final CEA. The estimated cost of treatment was $127.47 for MP, $142.20 for MP+UFH, and $169.40 for MP+LMWH. The average cost per quality-adjusted life-year for different strategies was $284.14 for MP+UFH, $338.39 for MP, and $722.87 for MP+LMWH. CONCLUSION: Although MP+LMWH is frequently considered the optimal prophylaxis for VTE risk reduction, our model suggests that MP+UFH is the safest and most cost-effective measure to balance VTE and hemorrhage risks in brain tumor patients at lower risk of hemorrhage. MP+LMWH may be more effective for patients at higher risk of VTE.