Patients diagnosed with glioblastoma multiforme (GBM) have a notoriously grim prognosis; median survival is only 13 months with multimodality treatment. The current standard of care for these patients is surgical resection followed by concurrent radiation and temozolomide (TMZ), and then by adjuvant TMZ. This regimen has been demonstrated to improve median survival by a modest 2.5 months. Thus, new interventions are desperately needed for patients diagnosed with GBM.
The Society for Neuro-Oncology (SNO) Annual Meeting is a venue for neuro-oncologists, radiation oncologists, neurosurgeons, and brain tumor researchers to discuss new research and advances in the management of primary and metastatic brain tumors. The 2006 Annual Meeting of SNO was held in Orlando, Florida, from November 16-19, 2006. On behalf of Medscape, Heather Gatcombe, MD, from Emory University School of Medicine in Atlanta, Georgia, spoke with Dr. Renato V. La Rocca, Director of the Kentuckiana Cancer Institute in Louisville, Kentucky, about new findings in the management of GBM that were presented at the meeting.
Medscape: What were the most important studies in GBM presented at SNO 2006?
Dr. La Rocca: For the first time, great strides are being made in the understanding of the biology of high-grade gliomas. For about 30 years, the biology of high-grade gliomas was poorly understood. There were some inklings that epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors were often abnormally expressed, but no one really understood what made astrocytic tumors tick. Over the last couple of years, we have seen an evolution particularly in the understanding of the "brain tumor stem cell." The fact that a brain tumor stem cell could actually be a real entity identifiable by CD-133 expression, and that this correlates with a significant angiogenic effect associated with vascular endothelial growth factor (VEGF) expression and production, opens new possibilities for targeted therapy.
The first exciting results of targeting VEGF in malignant glioma come from studies conducted by Vredenburgh and colleagues,[4,5] from Duke University. They studied the effect of bevacizumab, a monoclonal antibody against VEGF, in patients with recurrent high-grade astrocytic neoplasms.[4,5] Preliminary results for bevacizumab in combination with CPT-11 demonstrated an approximate 60% response rate.[4,5] These results have been replicated at other institutions.[6,7] One of the most difficult questions right now is: "What is the optimal dosing schedule for bevacizumab?" This remains an open question even for treatment of tumors outside the brain such as colon and lung tumors.
Medscape: You presented an interim analysis of a phase 2 study evaluating the combination of BCNU (carmustine) wafers placed within the surgical cavity after resection, followed by concurrent TMZ and radiation and then by adjuvant TMZ in patients with newly diagnosed high-grade gliomas. Can you please describe the study and results?
Dr. La Rocca: This interim analysis of a phase 2 study was designed to document safety of this quadruple modality regimen. So far, the results are intriguing, but it is important to note that they are very preliminary. We treated a patient population that is similar, but not identical, to the population treated by Stupp and colleagues. We added a fourth therapeutic modality to the Stupp protocol: local chemotherapy with BCNU wafers. BCNU wafers have shown a modest benefit compared with placebo wafers in patients with newly diagnosed brain tumors receiving radiation therapy. Westphal and colleagues reported a median survival time of 13.9 months with BCNU vs 11.6 months with placebo. Essentially, we are adding on to what has become the current standard of care; this is the next logical step. In our interim analysis, with only a 10.4-month median follow-up, median survival was 18.6 months in the 35 patients we studied, and adverse effects were consistent with those reported in previous studies.[2,9,10] These results are promising, but a randomized phase 3 study is needed to validate a true benefit in newly diagnosed patients with surgically resectable high-grade glioma.
Our study introduces the concept of quadruple multimodality therapy for the management of brain tumors: surgery, radiation, systemic therapy, and localized chemotherapy. We could then possibly consider adding a fifth modality, which would probably be an antiangiogenesis inhibitor. I think everyone is anxiously awaiting the results of the UCLA group's phase 1 study of bevacizumab with radiation and TMZ. Ultimately, there are still many unanswered questions in the realm of multiagent targeted therapies.
Medscape: There were a number of phase 1-2 trials presented at SNO 2006 that investigated the combination of TMZ with targeted agents such as bevacizumab and imatinib.[11,12] Will this become the future standard of care for newly diagnosed malignant glioma patients?
Dr. La Rocca: I think these targeted agents will have a role. TMZ has relatively modest toxicity, but its overall efficacy will have to be confirmed over time. Prados and colleagues, from UCSF, presented their recursive partitioning analysis, and if you consider the Stupp data in that context, TMZ may not have that large of an effect. I'm not trying to take away from TMZ and the impact that it has had in brain tumor management, but the question that has been presented to neuro-oncologists here at SNO is whether they would consider conducting a phase 3 study without TMZ in the control arm. I would, but the majority in the audience answered "no."
A targeted agent that I didn't hear much about at SNO, but that I am curious about, is the oral protein kinase C inhibitor enzastaurin, which has been shown to have some interesting antitumor activity. Fine and colleagues[14,15] at the National Cancer Institute are currently completing a phase 2 study.[14,15] A company-sponsored registration trial is underway comparing enzastaurin with CCNU chemotherapy in patients with recurrent glioma, and the results will probably be reported next year. This is another targeted oral agent that will be interesting to watch.
Medscape: At this point, is it more important for glioblastoma research to focus on localized or systemic therapeutic management?
Dr. La Rocca: I think the most important thing at this point is to work out the biology of these tumors, in order to develop more targeted therapies. I think the BCNU wafer is an interesting product because it allows you to bypass a lot of the barriers to delivery of therapy; you are able to provide therapy immediately after surgery when you have relatively minimal disease.
In a perfect world, I would like to see the BCNU wafer used as a platform for other agents; alternatively, I would like to explore the possibility of increasing the dose of BCNU in the wafers. Once upon a time, there was a phase 1 study by Olivi and colleagues from Emory University that investigated increasing the dose of BCNU in the wafers. They were safely able to increase the dose to a BCNU concentration of 20% (by weight of BCNU) within the 200-mg wafers without significant systemic toxicity. I think it would be interesting to continue looking at that approach.
Medscape: What is the current standard of care for recurrent GBM?
Dr. La Rocca: The standard of care is resection, if feasible, with possible placement of BCNU wafers, followed by some form of systemic therapy, ideally as part of a clinical trial. When possible, brain tumor tissue should always be collected for possible molecular and biologic correlates. If resection is not possible, I would advocate that all patients be placed on a clinical trial. I'm impressed enough with the CPT-11/bevacizumab data (now confirmed in abstracts from 2 other institutions in addition to Duke) that I would probably put a patient with recurrent GBM on that regimen outside of a clinical trial, provided that the patient's insurance would be willing to cover the bevacizumab.
Medscape: What exciting new data have emerged from preclinical research?
Dr. La Rocca: In my opinion, the brain tumor stem cell research is very exciting. We are trying to find out if it really does exist, what it is, and what the implications are for the biology of these tumors. The other thing we need to understand is the biology of the "virgin" brain tumor stem cell that has not been exposed to therapy and the biological functionality of the brain tumor stem cell after radiation and/or chemotherapy. The question is: are there genetic mutations that ultimately define the clinical behavior of brain tumors?
Medscape: There has been a correlation identified between a number of molecular alterations and clinical responsiveness to therapy. In particular, Hegi and colleagues[17,18] have demonstrated that patients with MGMT promoter methylation are more likely to respond to alkylating agents and that this corresponds with an improvement in overall survival (21.7 months with TMZ and radiation therapy vs 15.3 months for radiation alone). Will there be assays available for clinicians to assess which patients are more likely to respond?
Dr. La Rocca: Yes, these pathways are very interesting, but I am concerned about tumor heterogeneity. Does methylation really correlate with the protein, and can we assume on that basis that the patient will respond to a targeted agent? What also concerns me is that many of these tumors are very heterogeneous, so you really have to perform molecular analysis in real time. One of the things that occurs frequently, for example, with lung cancer is that a tumor sample is taken and analyzed 3 years before the patient receives a targeted agent. Subsequently, the patient has 2 resections, radiation, and chemotherapy, which means that we don't really know in real time what is going on at a molecular level. In addition, one must consider the heterogeneity of expression in these cells and that this may vary from metastatic site to metastatic site.
We will need multitargeted therapy to optimally manage high-grade brain tumors. I think many of the investigators at SNO appropriately noted that we are eventually going to have a tumor molecular profile for each patient at the time of his or her diagnosis, and we will be able to give each patient different targeted therapies simultaneously based on the profile. This is also the case with HIV. HIV cannot be controlled with one drug alone; rather, the virus needed to be targeted at multiple levels simultaneously. Hence, HIV changed from a devastating illness that killed affected patients in 2 years to an almost chronic disease. One of our goals as neuro-oncologists is to likewise transform brain tumors into a chronic disease.
Molecular assays are currently tremendously expensive. I think over time, as costs drop, you will be able to send a resected tumor specimen away, a kit will be done, and a profile analysis will be available for review in 2 weeks. From that list, you will then choose, for example, 6 out of 8 available different targeted therapies.
Medscape: When do you think that will be?
Dr. La Rocca: With unlimited time and unlimited money, I would say 5 years. In reality, it is more likely to take 10-20 years.
Medscape: Is there anything else you would like to add?
Dr. La Rocca: I think we are on the threshold of making significant inroads into understanding the biology of malignant gliomas, and the insights gained may be applicable to other tumor types. I am very happy that the Genome Project is including glioblastoma as one of the first 3 malignancies for the pilot phase of "The Cancer Genome Atlas." I believe we are going to see more focused research, not only by academic researchers but also by the pharmaceutical industry, on novel targeted and antiangiogenesis agents, many of which are orally administered.
Disclosure for interviewer: Heather G. Gatcombe, MD, has disclosed no relevant financial relationships.
Disclosure for interviewee: Renato V. La Rocca, MD, FACP, has disclosed that he serves on the advisory boards of Genentech, Amgen, Lilly, and MGI Pharma. Dr. La Rocca has also disclosed that he serves on the speaker's bureaus of Genentech, MGI Pharma, and Bristol-Myers Squibb. Dr. La Rocca has also disclosed that he owns stock in Genentech, Amgen, and Novartis.