Glioblastoma Part II: Future Directions

Abstract

Although uncommon, “brain cancer” is one of the most feared diseases that afflict human beings. While still regarded as one of the most deadly forms of primary malignant brain neoplasm, recent advances in the treatment of Glioblastoma Multiforme (GBM) have offered new hope for patients, families and clinicians. In the first part of this two-part evidence-based review, we focused on the multidisciplinary advances that have established the current standard of care practice in the management of GBM. The second part discusses ongoing research efforts, both ongoing clinical trial efforts as well as some of the newer technologies that are forming the promise of the future.

Introduction

Glioblastoma (GBM) remains one of the most deadly forms of primary malignant brain cancer. With an estimated 12,000 new diagnoses, GBM also makes up the majority of the 22,000 expected cases of primary malignant brain cancer in the United States in 2009¹. Due to the relative prevalence of GBM among malignant primary brain cancer and the short median survival, most of the ongoing research efforts in primary malignant brain cancer are focused on patients with this disease. In this paper, we will look to the future of neuro-oncology; including the therapies and technologies that are currently under development. Although at present, our ability to significantly alter the natural history of this disease is limited for the majority of our patients, the pace of development of novel drugs as well as novel technologies leave one with a sense of guarded optimism.

Radiology/Imaging Considerations

Advances in the field of neuro-radiology have occurred in many areas. The use of more powerful magnets (such as 3 Tessla MRI scanners) have allowed for more precise imaging (especially with vascular structures) as well as more accurate perfusion (blood volume/flow), spectroscopy and functional mapping. In addition, the 3 Tessla MRI scanner can acquire images in a shorter amount of time compared with the more standard 1.5 Tessla scanner. A second area of development is the use of concurrent PET scans for determination of metabolic activity of abnormal enhancing lesions on brain MRI. There are suggestions that this can be a helpful modality not only in initial diagnosis, but also in differentiating recurrent tumor from pseudo-progression (treatment-related change).

The use of alternative contrast agents, such as ferumoxytol, is adding an interesting new tool in MRI interpretation. Currently, ferumoxytol is utilized as a contrast agent in patients with severe renal impairment and, more generally, as a form of iron replacement in patients with documented iron deficiency. However, its use in the setting of evaluation of new enhancing lesions is showing promise in differentiating true tumor progression from pseudo-progression².

Neuro-Surgical Considerations

Although there will likely never be a clinical trial focused on a randomized comparison of biopsy versus gross total resection for patients with newly diagnosed Glioblastoma, the available literature strongly suggests that a maximal resection which does not injure the patient, and improves both symptom control and survival. The importance of obtaining a maximal safe resection has led to the development of a number of newer surgical technologies discussed in the previous paper, including image guidance, functional mapping and awake craniotomy. These more advanced technologies, which are expensive, as well as a team of practitioners experienced in the care of patients with brain cancer are likely reasons for study findings that suggest improved patient outcomes at institutions which see a large number of patients (at least 42 admissions/year) compared with those seeing a fewer number of patients (six or fewer/year) ^{3, 4}.

Intra-operatively, the wall of the resection cavity is typically visualized through the operating microscope, allowing the surgeon to visually differentiate grossly normal brain from tumor-involved brain. An approach which has been developed over the past decade in Europe involves the use of a novel agent called 5-aminolevulinic acid (5-ALA). This drug, which is a relatively non-toxic, oral elixir given to the patient to drink several hours before surgery, is taken up by tumor cells and synthesized into protoporphyrin IX, a substance which naturally fluoresces under blue-violet light. In several trials, using intraoperative visualization of fluorescing tumor through a specialized operating microscope, this technique has been shown to significantly increase the extent of safe resection and is effective even in patients who have had prior radiotherapy or chemotherapy^{5, 6, 7}. Trials are currently ongoing in the United States.

Another technology which offers promise of increasing the extent of resection in a different way is the use of intraoperative MRI scanners. Frequently during the surgical resection of large and/or irregular shaped tumors, which have caused a significant amount of brain swelling, there occurs a progressive collapse of the surgical cavity as the tumor pressure is decreased. Although the current methods of tumor mapping give a very precise 3-dimensional picture of the tumor pre-operatively, these maps do not “follow” the ever-changing brain during surgery, and ultimately, the surgeon is left to visualize the cavity walls through the operating microscope as best as he or she can. Intraoperative MRI scanning potentially allows the surgeon to take a “second look” at the time of surgery, allowing for removal of areas of residual tumor which may not have been visible through the microscope. Studies have suggested an improvement in extent of resection with this technique⁸.

Radiation Oncology

In light of the modest benefit of currently available salvage therapies for patients with recurrent Glioblastoma, re-irradiation as a potential salvage therapy has been explored. At the time of initial treatment, most patients receive a near maximal “safe” dose of radiation to the tumor bed, usually in the area of 54 to 60 Gray, with a surrounding margin of decreasing dose. A major challenge in re-irradiation strategies is exposing healthy brain to supertherapeutic doses resulting in significant rates of radionecrosis and resulting morbidity. Stereotactic radiosurgery (SRS) allows the radiation oncologist to very precisely target a small area with a steep drop in the delivered radiation dose outside of this area; additionally the total dose can be given in a single or a few treatments. Several single institution reports have suggested improved outcomes with the use of SRS at recurrence for selected patients with GBM; however treatment strategies have varied from 15 Gray in single fraction approach up to 35 Gray in multiply fractionated treatment. Notably a number of these patients did have tumor debulking surgery at the time of recurrence^{9, 10, 11, 12}. One study which treated patients to a dose of 35 Gray in five treatments, showed response in four patients, stable disease in five and progression in six patients (total of 15), with no decrease in quality of life (measured by the EORTC-QLQ) in 10 patients for a median of nine months¹³. While suggestive, these data need to be confirmed in larger studies. Also, tumor recurrence which is of large size or involves eloquent areas of the brain can limit the general applicability of this strategy.

Neuro-Oncology/Medical Oncology

Laboratory experiments have shown that chemotherapy-resistance in Glioblastoma tumor cells can be overcome with more “metronomic” dosing of chemotherapy drugs. Specifically, if the cells are dosed with lower doses of chemo given daily for an extended period compared with high daily doses for a limited period (five days), they are killed more readily. The question of schedule-intense dosing of Temozolomide is being evaluated in RTOG 0525, which, after surgery and radiation with daily Temozolomide, randomized patients to either a standard 5-day on 23 day off dosing schedule or a 21-day on/7-day off schedule. This study has completed accrual and results are expected to be released this year.

Other approaches using novel targeted therapies added to standard Temozolomide based therapy are being explored. Cilengitide, a novel integrin inhibitor, has demonstrated to be fairly non-toxic and with promise in early stage trials, is currently being studied in treatment trials for newly diagnosed patients. Integrins are found not only on the surface of tumor cells, but are also an important component of angiogenesis, or new blood vessel generation, an important process facilitating tumor growth. Two other inhibitors of angiogenesis, Cedirinib¹⁴ (RTOG 0827) and Bevacizumab (RTOG 0825, and other trials) are also being tested in the initial treatment setting as well.

Recent advances in the understanding of the interaction between Glioblastoma and the patients’ immune system have led to development of novel immunotherapeutic approaches. Historically, it had been proposed that tumors grow because immune surveillance fails to recognize and destroy tumor cells. More recently however, it has been shown that tumors “hijack” elements of the normal immune system; this immune cooperation can aid in growth. The essential idea behind immunotherapy is to generate an immune attack against the tumor cells while preserving normal brain tissue. Although animal models have suggested efficacy and initial human trials have shown promise, more definitive studies of efficacy of immunotherapy are still ongoing¹⁵. Several approaches including anti-EGFR (epidermal growth factor receptor) vaccine, anti-heat-shock protein (HSP) vaccine, dendritic cell vaccine, and autologous tumor vaccine (TVAX) are currently being tested.

A treatment strategy that directly addresses the relative impermeability of the blood brain barrier (BBB) involves intra-arterial chemotherapy combined with blood brain barrier disruption (BBBD). Administering chemotherapy into the artery that directly feeds the tumor (the carotids and one of the two vertebral arteries) takes advantage of the “first pass effect” and allows a higher concentration of chemotherapy in the immediate region of the tumor, before becoming diluted in the systemic circulation. This method of administration of chemotherapy, intra-arterial chemotherapy, can be used alone or in combination with concurrent blood brain barrier disruption. The BBB is essentially a thin physiologic barrier or filter which separates the blood flowing to the central nervous system from directly bathing the brain parenchyma and cerebral spinal fluid. This functions in health to keep harmful particles (pathogens, toxins, etc.) out from the sensitive brain tissues, thereby preventing toxicity which would otherwise occur. In disease, however, the BBB prevents many chemotherapy molecules from entering the brain and, in so doing, can significantly reduce the effective drug dose that tumor cells residing within the brain parenchyma are exposed to. However, the BBB can be temporarily disrupted or opened by the infusion of mannitol, thereby facilitating the passage of chemotherapy molecules and allowing much higher concentrations to reach the tumor cells. Experiments have shown that the concentration of intra-arterially infused chemotherapy reaches concentrations 2× higher within experimental tumors and 5× higher in brain immediately surrounding tumor compared with contralateral uninvolved brain. When this is preceded by mannitol disruption, concentrations reach 9× higher within experimental tumor and 12× higher in brain immediately surrounding tumor compared with contralateral uninvolved brain¹⁶. While this approach has the potential to deliver much higher chemotherapy doses directly to the tumor and surrounding brain and, thus impacting more tumor cells, it has achieved only modest results in treatment of recurrent Glioblastoma, likely due to the modest efficacy of drugs such as Carboplatin. Newer drugs are currently in development.

Conclusion

This review is not meant to be inclusive of all new strategies and developments ongoing in neuro-oncology. Rather, the focus has been on those technologies which offer promise to improve quality of life and/or survival in the near future. Our hope is that as these technologies mature and new approaches develop, that we will have more promise to offer our current and future patients. With that in mind, the authors offer their ongoing appreciation and thanks to all those patients who have volunteered for clinical trials, for the hope of improved outcomes for themselves and the certainty of improving outcomes for those who will follow.

Biography

Michael E. Salacz, MD, practices Neuro- Oncology, Medical Oncology & Palliative Medicine, and is the Medical Director at Saint Luke’s Brain Tumor Center in Kansas City, Mo. Kenneth R. Watson, DO, practices Anatomic Pathology and David A. Schomas, MD, practices Radiation Oncology with St. Luke’s Health System. This is part two of a two-part series.

Contact: msalacz@saint-lukes.org