Malignant Gliomas in 2005: Title and subTitle BreakWhere to GO From Here?

Brain tumor is one of the diagnoses most feared by patients, physicians, and even oncologists. Their fear is justified. More than half of the 18 400 primary malignant brain tumors diagnosed each year in the United States are malignant gliomas¹ that not only confer high risk for death and severe disability, but also steal what is held so highly as the essence of human life: the mind and spirit. In this issue of JAMA, Chang et al² use data from the Glioma Outcomes (GO) Project to provide a “report card” on the patterns of care in patients with newly diagnosed malignant gliomas; unfortunately, the grades are sobering. Consequently, this is an appropriate time to reflect on the past and current status of glioma treatment and suggest where to go from here.

Seventy-seven years ago, also in JAMA, Dandy³ described the hemispherectomy, removal of half the brain—the most radical treatment to date for malignant gliomas—that he hoped would extend life and sometimes “offer a cure otherwise not obtainable.” At surgical inspection, Dandy could not find all the neoplasm to be “extirpated,” and he noted that tumor tissue invaded deep into the midline of the brain and also found that the glioma infiltrated the overlying dura. Even worse, in the removed hemisphere, grossly visible cancer could be found well beyond the primary site. Ultimately, the few patients who did survive this surgery died of recurrent glioma. The lesson learned was that malignant gliomas do not have a discrete margin or even a penumbra.

Decades later, in the most ominous glioma—glioblastoma multiforme—correlative postmortem pathologic examinations and antemortem computed tomography confirmed conclusively that these malignant tumors infiltrate diffusely centimeters beyond the primary lesion, sometimes into the contralateral hemisphere, and their extent escapes detection even by modern neuroimaging.⁴ Clearly, malignant gliomas are simultaneously a localized and regionally metastatic cancer at or soon after diagnosis and are not surgically curable.

Today malignant gliomas are categorized as World Health Organization grade III or IV cancers. The largest percentage are the astrocytomas, glioblastoma multiforme (grade IV) or anaplastic astrocytoma (grade III), followed by mixed anaplastic oligoastrocytoma (grade III) and anaplastic oligodendroglioma (grade III), and only rarely anaplastic ependymoma (grade III).⁵ These gliomas occur most frequently in persons aged 45 to 55 years and are more common in men than in women. As previously established by the GO Project, the overall median survival from diagnosis for patients with malignant gliomas is 48.2 weeks.⁶ In individuals with glioblastoma, median survival is 40.9 weeks; those with grade III gliomas have a median survival of 73.4 weeks.

Following diagnostic magnetic resonance imaging (MRI) for patients with a suspected malignant glioma, the National Comprehensive Care Network Guidelines recommend, if feasible, maximal surgical resection to mitigate symptoms and to establish a diagnosis, or if not feasible, at least an open or stereotactic biopsy.⁷ Whether the extent of resection correlates with survival is controversial.^{6 ,8 - 9} Regardless, local field irradiation is recommended after surgery, and chemotherapy should then be administered as adjuvant therapy or at the time of tumor relapse.⁷ Guidelines from the American Academy of Neurology advise further that routine, prophylactic anticonvulsant use is not warranted in patients with newly diagnosed brain tumors. In patients who have not experienced a seizure, tapering anticonvulsants after the first week is appropriate.¹⁰ But do clinicians practice what these guidelines recommend?

The data presented by Chang et al from the GO Project² suggest that current clinical practice often does not follow guidelines or evidence. While nearly all patients in this study underwent diagnostic MRI, 30% had no resection of the tumor except biopsy, 13% did not undergo conventional radiotherapy, and 46% did not receive any chemotherapy. Eighty-two percent of patients were known to be receiving postoperative anticonvulsants, despite that only 32% were known to have preoperative seizures. More disappointingly, only 15% of patients participated in clinical trials, yet 29% sought alternative therapies and 59% received care at an academic center. Only 8% of the participants received perioperative antidepressant medication, despite the prior GO Project determination that 93% and 91% of patients reported symptoms of depression immediately postoperatively and 6 months later, respectively.¹¹ Just 7% received perioperative prophylactic low-dose heparin, even though the incidence of deep venous thrombosis within 6 weeks after surgery might be as high as 60%.¹²

Perhaps the GO findings presented by Chang et al do not accurately portray the current practice patterns in neurooncology, since the study has several limitations. The sample of 565 patients does not include all patients from 52 clinical centers, and at some sites, less than 50% of those eligible were enrolled.¹¹ In addition, the authors acknowledge that patient compliance in the completion of 7 separately mailed questionnaires cannot be ensured. Furthermore, the analyses are limited largely to univariate comparisons, without thorough multivariate analyses or detailed analyses of how the care patterns changed over time or were related to survival. Nevertheless, this is a straightforward observational study, with patient characteristics typical of those seen in clinical practice. The findings unfortunately appear to reflect reality.

Thus, is it reasonable to conclude that the GO Project demonstrates the current therapeutic nihilism in managing malignant gliomas? Radiotherapy does improve survival in high-grade astrocytomas, but only by 22 weeks.¹³ Chemotherapy regimens used at the time of the GO Project, such as carmustine or procarbazine, lomustine, and vincristine, have been found to have minimal or no survival benefit in malignant gliomas and do not cure these patients.^{14 - 15} Furthermore, the uninterrupted use of anticonvulsants noted in the GO Project, along with the low rates of use of antidepressants or prophylactic heparin, almost suggests a disinterest in doing much for these patients. The finding that just 15% of patients at academic medical centers enrolled in clinical trials is alarming. Whether this apparent apathy stems from patients, their families, or physicians not being interested in or not having opportunities to participate in clincal trials is unclear. The fact that twice as many patients pursued alternative therapies hints that many patients or their families do want to pursue whatever treatment they can for their cancer.

Despite this apparent therapeutic inertia, there is cause for cautious optimism since the conduct of the GO Project from 1997 to 2000. First, in a recent European Organisation for Research and Treatment of Cancer randomized phase 3 trial for patients with newly diagnosed glioblastoma multiforme, individuals treated with oral temozolomide during and after radiotherapy survived for a median of 15 months.¹⁶ Their health status and quality of life are likely as good as or better than prior patients treated with nitrosoureas (carmustine and lomustine).¹⁷ Second, in patients with anaplastic oligodendroglioma, whose tumor specimens have loss of heterozygosity at chromosome loci 1p and 19q, studies have revealed increased overall survival and also tumor shrinkage from chemotherapy.^{18 - 19} And third, the explosion of research in tumor genomics and proteomics as well as novel, targeted chemotherapeutics in other cancers offer hope of progress, if such targeted therapies are developed specifically for brain tumors and are effective.

This optimism, while necessary, is insufficient to improve care patterns and survival for patients with malignant glioma without an aggressive clinical research agenda. The reasons for this are compelling. For any given person, the lifetime risk of dying from a brain tumor remains almost 1 in 200.²⁰ The National Cancer Institute presently supports 3 limited brain tumor clinical trials consortia (North American Brain Tumor Consortium, New Approaches to Brain Tumor Therapy, and Pediatric Brain Tumor Consortium) for the phase 1 and phase 2 evaluation of new therapies. Funding for these consortia is relatively modest, and the number of sites with comprehensive expertise is far too few from the perspective of a patient debilitated by a malignant glioma. These consortia also emphasize drug therapies rather than entirely new technologies only alluded to in this study, nonchemotherapeutic approaches, or high-end biological studies. In these consortia and elsewhere, most treatments offered in brain tumor clinical trials are “hand-me-downs” from those used for other cancers, those developed by privately sponsored drug companies, or both.

Where should treatment of gliomas go from here? Neurooncology requires a major paradigm shift and substantial changes in treatment and research involving malignant gliomas. Wider availability of novel approaches and increased cooperation between academic institutions and community centers must occur to improve care patterns for patients with malignant glioma. In addition, for any clinical trial, correlative biological studies of tumor specimens need to be wedded to the trial, particularly when end points may be biological change rather than tumor reduction demonstrated on MRI. As oncology takes on increasingly specific, targeted approaches, it is inappropriate to continue rolling out new therapies indiscriminately and often conclude that they are not effective in “malignant gliomas,” a molecularly heterogeneous group of tumors lumped together based on light microscopy. Some treatments may be highly beneficial to a select few patients, yet ineffective in many others. At the same time, phase 1 trials in oncology that have traditionally excluded patients with brain tumors should be made more widely available to those with malignant glioma, particularly now with the advent of anticonvulsants that do not induce cytochrome P450²¹ and will not interact with many experimental compounds. In addition, understanding of the etiology of brain tumors must be improved.

There are few proven risk factors for the development of brain tumors. It is difficult to imagine advancing cures unless the genetic, environmental, dietary, other risk factors,and their interactions that cause brain tumors are more clearly established. Biological studies need to be incorporated into these epidemiologic investigations to enhance the informativeness of these studies. Increased funding via governmental grant mechanisms or philanthropic foundations will be paramount for the progress needed to achieve this progress. Advancements for patients with malignant glioma have been negligible, and there is a real risk of going nowhere by simply continuing to travel the same path.