CHAPTER 64 Challenges and Opportunities in Future Meningioma Research and Care

INTRODUCTION

There has never been a more exciting time in meningioma research and care. As analytic tools improve and interest grows, great strides can occur toward understanding and treating meningiomas. Patient advocacy and funding agency interest will help to generate better and better paradigms for management and the analytic tools are increasingly available. This chapter discusses some future possibilities in basic and translational research, pathology, imaging, surgical management, radiation, chemotherapy, and outcome analysis.

BASIC AND TRANSLATIONAL RESEARCH

Basic research is the engine that drives the future development of medical care. For meningiomas, it involves not only molecular biology but also epidemiology, new therapeutic agents, non-invasive surgical techniques, side effects of treatment, and a host of other topics. Often the greatest improvements are made when techniques allow a definitive to answer to some long-standing questions. We now have very powerful molecular techniques, and many of them are just awaiting application to meningiomas. Modern molecular biology and genetics can significantly support research on the oncogenesis, epidemiology, diagnosis, treatment, and follow-up of meningiomas. At present, techniques of single-nucleotide polymorphism (SNP) analysis, high-throughput screening for molecular profiling, and proteomics have been applied to other tumors with great success. Only personnel and interest among investigators are needed to apply these techniques in meningioma research. Here are some of the questions that should be answerable in the next 10 years:

EPIDEMIOLOGY

One of the most important areas for meningioma research is epidemiology, including molecular epidemiology. Despite almost a century of ongoing research, there are still numerous unknowns regarding the epidemiology of meningiomas. A striking example is that we still do not know which meningiomas will grow after diagnosis and which will not, and the clinician regularly faces several of these dilemmas in daily practice. Classical epidemiology studies such as the INTERPHONE study and other large-scale studies of causal or permissive factors in meningiomas are important contributions to the literature. The INTERPHONE study is the largest case control study to date to examine the risks of mobile-phone use and includes more than 2400 meningioma cases. Also in 2005, the NIH funded a very large study led by Dr. Elizabeth Claus, which will begin to answer several ongoing questions in meningioma pathogenesis:

In recent decades, we have experienced very significant advances in molecular biology. Novel molecular and genetic techniques, including large-scale–high-throughput techniques have also revolutionized epidemiological studies. Linkage analysis to discover gene variants associated with susceptibility to a disease and population-based association studies, which compare affected and normal populations, are the two basic methods in genetic studies. In the last decade, these studies have revealed the basis for several polygenetically inherited metabolic and vascular disorders such as diabetes, hypertension, and subarachnoid hemorrhage. Such techniques can also potentially shed light into may aspects of meningiomas. A very striking example is radiation induced meningioma development. Ionizing radiation is an established risk factor for development of meningiomas and other tumors. Epidemiological studies on unique cohorts, such as the tinea capitis cohort in Israel. This study population consists of individually who had received a dose of cranial irradiation to induce temporary epilation to treat tinea capitis, and includes more than 500 families who have been followed for over 50 years. Recent epidemiological studies, such as the one by Flint-Richter and Sadetzki in 2007 have indicated that radiation susceptibility may by familial. In 1997 Gilad and colleagues showed a defect in the ataxia telangiectasia gene in the affected population. In addition, the “childhood cancer survivor study” included patients who developed brain tumors after irradiation for childhood lymphoma in a similar cohort from the United States. Comparison of such studies can shed light on both demographical/clinical and biological parameters that can be causative or permissive of meningioma development. The application of novel techniques will certainly expedite new discoveries.

IMAGING

Magnetic resonance (MR) is an important advance in brain imaging, and the possibilities for its application are only now being explored. The issue is not only imaging the tumor location and size but also analyzing tumor relationship to the brain parenchyma including reasons for edema and whether white matter tracts have been violated. MR can also assess the changes that occur after tumor removal. Meningiomas therefore provide an important model for analyzing brain plasticity from compressive effects on brain and how the brain recovers from them.

In some centers, volumetric MR techniques allow automated segmentation and analysis of meningiomas and other benign tumors. This facilitates the monitoring of a patient whose tumor is simply being observed.

The use of positron emission tomography (PET) scanning as new ligands become available may significantly change meningioma imaging, as the somatostatin receptor is so widely found in these tumors. Some of the questions that can be answered concerning imaging for meningiomas are:

PATHOLOGY

The pathology of meningiomas continues to be fascinating and understudied. Meningiomas are mesenchymal tumors and the morphologic findings are more vague than those observed in ectodermal tumors. Although not as pronounced as in gliomas, there is still some interobserver variability in the subclassification of meningiomas, especially in the diagnosis of atypical and anaplastic variants. The atypical and malignant meningiomas are particularly important as a group, and their nature and outcomes deserve more comprehensive study.

Although the World Health Organization (WHO) classification into three grades provides a rough estimate of future clinical behavior, we have observed an increased understanding and better organization of histomorphologic findings between the 1993 and 2000 WHO classifications. However, the 2007 WHO classification was largely identical to its predecessor, indicating a saturation of morphologic capabilities. Yet, there is still a very significant overlap between each pathologic subgroup. Unexpected clinical behavior is observed in a significant proportion of cases, such as 7% recurrence rate that increases as a function of time, sudden changes in growth characteristics, rapid growth, metastasis, and brain invasion in benign cases. Therefore, we can conclude that the current histopathologic stratification scheme is useful but should be supplemented with additional indicators to predict clinical behavior and outcome accurately. An ever increasing mass of information on molecular biology and genetics holds significant potential to supplement morphologic information to improve or to replace existing classifications schemes, as in the example of breast cancer.

Questions relevant to pathology include:

SURGERY

Surgery for meningiomas has improved remarkably in the last 20 years. For convexity and parasagittal meningiomas, these techniques include the use of navigational systems, respect for the sagittal sinus, and understanding of the importance of preservation of veins; for skull-base meningiomas, they include a plethora of new techniques for safe approach and resection and the development of endoscopic approaches.

RADIATION

As surgery has improved for meningiomas, so has radiation. The diffuse external beam therapy of 20 years ago has given way to conformal radiation techniques, which have much less collateral damage to brain and surrounding structures. These techniques include stereotactic radiosurgery including Gamma-Knife, LINAC, and proton beam therapy; fractionated stereotactic techniques including Novalis shaped beam therapy; and general awareness of the importance of preserving such structures as the optic nerves.

CHEMOTHERAPY

Chemotherapy has not generally been used for meningiomas. In the late 20th century, antiprogesterone and antiestrogen therapies were attempted without success. Other chemotherapeutics agents such as hydroxyurea and β-interferon have also been tried with no consistent benefit. As chemotherapy enters a new age, however, there may be a new set of agents that would be useful, especially targeted agents such as antigrowth factor and antiangiogenic agents.

BIOLOGICAL THERAPEUTICS

Demonstration of hormone receptors on meningiomas led to trials of hormone therapy. Mifepristone (RU486) and tamoxifen have been tried in clinical trials without major clinical success. Somatostatin analogues have also been tried against meningiomas. The role of hormone receptor status in meningioma oncogenesis and maintenance has yet to be determined. As mentioned in the preceding text, antiangiogenic therapeutics also carry great potential for meningioma treatment. Targeted therapeutics such as small molecule inhibitors have emerged as a new field in oncology in the last decades. Currently there are no clinical trials that have tested these drugs in meningiomas. The use of immunotherapy for meningiomas is limited to the immunological response modifier interferon, which also has direct antitumoral activity. Experimental and small clinical studies have indicated possible activity of interferon-alpha-2B against meningiomas. The mode of action of interferon has yet to be more clearly identified. Other aspects of immunotherapy against meningiomas have not been explored either. Gene therapy is another area of great potential in meningioma treatment. Although the initial idea was the replacement of defective or missing genes, most current experimental therapeutics in the field of neuro-oncology are focused on selective suppression or killing of tumor cells. The mechanism of action of most gene therapy strategies is fundamentally different from other available treatment modalities such as surgical resection, chemotherapy, and radiotherapy. Meningiomas have mostly been out of focus of gene therapy efforts, mostly due to the benign nature of the tumor and the existence of several effective treatment methods. There are only very few preclinical studies that have focused on gene therapy for meningiomas.

OUTCOME ANALYSIS

Cancer care in general is spending a great deal of time on outcomes as a way of modifying and improving our care. Using well-established outcome measures for neurologic disorders, we can begin to see what features of a meningioma make the patients most unhappy and what can be done about these. Some questions for outcome are:

SUMMARY

The future for meningioma studies is very bright. Many of the basic and other concepts developed in other tumors can be applied to them. If we attract good people of all ages and disciplines into meningioma studies, we can move the field forward significantly. We hope that you as a reader of this book will help to do that.