Malignant glioma, the most common primary central nervous system (CNS) tumor in adults, remains one of the greatest therapeutic challenges in oncology today due to the limited impact of conventional cytotoxic therapies on overall survival for patients with these tumors. Although surgery and external- beam radiotherapy (XRT) can prolong survival, the value of adjuvant chemotherapy has been negligible for most malignant glioma patients. The exception has been those patients with anaplastic oligodendroglioma and accompanying chromosomal 1p and 19q loss-a fairly uncommon subset of malignant glioma patients who respond very favorably to alkylatorbased chemotherapy. However, an important advance for patients with glioblastoma multiforme (GBM), the most common type of malignant glioma, was recently achieved. In a multinational phase III trial, newly diagnosed GBM patients who were randomized to receive XRT plus daily temozolomide followed by six monthly cycles of temozolomide, had a significantly improved survival rate compared to patients treated with the historical standard of care-XRT alone. Thus, for the first time, a meaningful clinical benefit for chemotherapy was prospectively demonstrated in newly diagnosed GBM patients. Nonetheless, the median progressionfree survival for patients treated with XRT plus temozolomide in this study was less than 7 months, and the overall survival was under 15 months. Furthermore, outcome for malignant glioma patients following recurrence remains abysmal, due to ineffective salvage therapies. Therefore, much progress is still critically needed. Locoregional Approaches: Uniquely Suited for CNS Tumors
Several factors contribute to the limited response of malignant gliomas to conventional cytotoxic therapies; these include inter- and intratumoral heterogeneity, high rates of de novo and acquired chemoresistance and DNA damage repair, and difficulties with delivery due to the blood-brain and blood-tumor barriers. In addition, despite the use of conventional, locally directed therapies, such as surgery and XRT, the vast majority of patients experience a recurrence at or adjacent to the site of tumor origin, indicating that failure to eradicate local tumor growth is a major factor contributing to poor outcome. In his review, Dr. Mamelak provides a timely and thorough review of many of the current promising, innovative locoregional therapeutic strategies for patients with malignant glioma. Locoregional approaches offer several important advantages over systemically administered therapies, including the possibility of achieving greater and more homogeneous distribution of therapy to the area of greatest risk of tumor recurrence while limiting systemic exposure and toxicity. In addition, local administration methods may facilitate the delivery of therapy along the white matter tracts frequently followed by malignant glioma cells as they infiltrate and progress. Tumor Targeting Therapeutics: A New Era
Decades of laboratory research have identified and characterized components of important signal transduc- tion pathways and other cellular markers that contribute to the malignant phenotype of many cancers. Many of these entities are now being therapeutically exploited in the treatment of a variety of cancers including malignant glioma. Monoclonal antibodies that specifically react with a given tumor cell marker represent one successful example of such therapy. Some monoclonal antibodies are successful as cancer therapeutics when administered "unarmed" such as trastuzumab (Herceptin, target = HER2/neu receptor), rituximab (Rituxan, target = CD20 antigen) and cetuximab (Erbitux, target = epidermal growth factor receptor [EGFR]), while others, such as ibritumomab (Zevalin, target = CD20 antigen) and tositumomab (Bexxar, target = CD20 antigen), are "armed" with a radioisotope for administration. Radioimmunotherapy, or the administration of a radiolabeled monoclonal antibody against a tumorspecific marker, has been a focus of clinical investigation for brain tumor patients as well. Large molecules, such as monoclonal antibodies, are unlikely to effectively penetrate the bloodbrain barrier; therefore, most studies have evaluated local administration strategies. For example, 81C6 is a murine immunoglobulin (Ig)G2b that specifically binds tenascin, an extracellular matrix hexabrachion glycoprotein that is expressed ubiquitously in high-grade gliomas and in breast, lung, and squamous cell carcinomas, but not normal, adult brain. Phase II studies in which iodine- 131-labeled 81C6 (131I-81C6) is administered into a surgically created resection cavity in patients with malignant glioma have been associated with encouraging rates of overall survival. In addition, 131I-81C6 is associated with a much lower rate of reoperation for radionecrosis than that reported for other strategies aimed at boosting radiotherapy to the primary tumor site, such as stereotactic radiosurgery or the implantation of I-125-labeled beads into the resection cavity. Currently a randomized, multicenter, phase III clinical trial is planned to further evaluate locally administered 131I-81C6 for malignant glioma patients. As described by Dr. Mamelak, convection- enhanced delivery (CED) is another innovative locoregional strategy currently being extensively evaluated for malignant glioma patients. Most tumor-targeting therapeutics currently administered via CED are composed of a ligand to a tumor-specific receptor that is chemically conjugated to a toxin, such as the exquisitely potent Pseudomonas exotoxin (PE). Upon binding to its receptor on the tumor cell surface, the ligand-toxin conjugate is internalized, and the toxin is released, thereby killing the tumor cell. These agents have proven to be highly effective as tumor-specific cytotoxins with highly encouraging long-term survivors noted; however, we have learned that effective delivery to the tumor bed via CED is a complex challenge. We evaluated the distribution of I-123-albumin coinfused with a toxin conjugate via CED in a series of patients. Surprisingly, very limited volumes of distribution were noted in the majority of CED infusions (unpublished data). As a result, a number of detailed criteria have been adopted regarding the placement of CED catheters in ongoing trials that appear to be significantly improving volumes of distribution. As discussed in the Mamelak review, a therapeutic agent targeting the interleukin-13 receptor, IL-13-PE, is now being widely evaluated in both a multicenter, randomized phase III study for recurrent GBM patients, and in a companion dose-escalation trial for newly diagnosed GBM patients who also receive XRT and temozolomide. Additional studies are currently evaluating a therapeutic agent targeting EGFR using a TGFalpha- PE conjugate, and a clinical trial evaluating a similar therapeutic specific for the tumor-associated EGFR mutant, EGFRvIII, is expected to initiate in the next several months. Viral Therapy: Dependence on Tumor-Specific Targeting
As reviewed by Mamelak, the use of locally administered viral-based therapeutics to treat brain tumors has been extensively investigated over the past several years, with unfortunately overall disappointing results. A recent twist to this approach is the development of oncolytic viruses, including common human viral pathogens, such as the adeno-, herpes- and reoviruses, which are genetically engineered to achieve selective virus replication and cytotoxicity in tumor cells while avoiding replication and damage to normal tissues. Similar to the success of monoclonal antibodies and toxin conjugates as effective cancer therapeutic agents, a critical component to the development of oncolytic viruses is the capability of these agents to interact efficiently and specifically with tumor cells. A promising example of such an oncolytic virus is a poliovirus variant, genetically engineered to replicate robustly in malignant glioma cells but not in normal human CNS cells. A clinical trial of this nonneuropathic, glioma-specific, oncolytic poliovirus recombinant, administered locally to patients with malignant brain tumors, is anticipated to begin in the next 1 to 2 years. Immunotherapy: A Promising Future for Brain Tumor Patients
Historically, enthusiasm for immunotherapeutic approaches to brain tumor patients has been curtailed for several reasons. Brain tumor patients have impaired innate T- and B-cell immune responses and are frequently on immunosuppressive corticosteroids. Furthermore, the CNS is regarded as an immunoprivileged site, and malignant gliomas are known to secrete immunosuppressive factors, such as TGF-beta. However, as presented in the Mamelak review, clinical benefit has been demonstrated with immunotherapeutic strategies for some brain tumor patients, and recent additional insights suggest that further advances may be possible. For example, evidence of cytomegalovirus (CMV) reactivation was recently demonstrated in a large proportion of high-grade gliomas, while no evidence of CMV infectivity was detected in surrounding normal brain samples or in brain tissue affected by ischemia or Alzheimer's disease. Dendritic cells, loaded with tumorspecific antigens, are capable of activating potent CD4+ and CD8+ T-cell-mediated antitumor immune responses, and a recently completed clinical trial utilizing dendritic cell vaccination against EGFRvIII at our institution has achieved very encouraging results. An update of this trial, utilizing dendritic cells pulsed against CMV antigens was recently initiated for newly diagnosed GBM patients. Conclusions The Mamelak review highlights many of the promising locoregional approaches currently under evaluation for patients with malignant glioma. The CNS poses unique obstacles that have contributed to limited activity of conventional cytotoxic therapies historically. Locoregional approaches may help overcome such obstacles and therefore represent a very important component of the cutting edge in neuro-oncology today.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Cairncross JG, Ueki K, Zlatescu MC, et al: Specific genetic predictors of chemotherapy response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473-1479,1998.
2. Stupp R, Mason WP, Van Den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005.
3. Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572-2578, 1999.
4. Gaspar LE, Fisher BJ, Macdonald DR, et al: Supratentorial malignant glioma: Patterns of recurrence and implications for external beam local treatment. Int J Radiat Oncol Biol Phys 24:55-57, 1992.
5. Reardon DA, Akabani G, Coleman RE, et al: Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20:1389-1397, 2002.
6. Shrieve DC, Alexander E 3rd, Wen PY, et al: Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 36:275-284 (incl discussion), 1995.
7. Sampson JH, Reardon DA, Friedman AH, et al: Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma with intracerebral infusion of the recombinant targeted toxin TP-38: Case study. Neuro-oncol 7:90-96, 2005.
8. Ochiai H, Moore SA, Archer GA, et al: Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus. Clin Cancer Res 10:4831-4838, 2004.
9. Cobbs CS, Harkins MS, Gillespie GY, et al: Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62:3347-3350, 2002.
10. Archer GE, Bigner DD, Friedman AH, et al: Dendritic cell vaccine for intracranial tumors I (DC VICTORI trial) (abstract IM-02). Neuro-oncol 6:341, 2004.