Hope for Glioblastoma: Resection and New Treatments

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Glioblastoma multiforme (GBM) is one of the most common brain tumors and is a significant cause of morbidity and mortality.1 Primary tumors of the brain occur in about 16,000 persons and account for around 13,000 deaths annually (a mortality rate of 6 per 100,000) in the United States.

Glioblastoma multiforme (GBM) is one of themost common brain tumors and is a significantcause of morbidity and mortality.¹ Primarytumors of the brain occur in about 16,000persons and account for around 13,000deaths annually (a mortality rate of 6 per100,000) in the United States.

Glial neoplasms account for 50% to 60% of all primary tumors of the CNS.² Of newly diagnosed intracranial neoplasms, about half are malignant and are associated with a remarkably dismal prognosis. Even though improvements have been made in chemotherapy, radiotherapy, and surgical intervention, the poor prognosis has not improved over the past 2 decades.

Glioblastoma predominantly develops in the cerebrum, but can be found anywhere in the brain, including the optic chiasm, brain stem, spinal cord, and cerebellum.³ Even when treated with surgical resection, chemotherapy, and radiotherapy, high-grade gliomas are associated with a survival time of only 1 to 3 years.⁴

"Not many studies are available that compare outcomes of the various serious malignancies following treatment," said Henry S. Friedman, MD, deputy director of the Preston Robert Tisch Brain Tumor Center and professor of neuro-oncology at Duke University Medical Center in Durham, North Carolina. "I would say, however, that GBM has a worse outcome compared with carcinoma of the lung but better than esophageal or pancreatic cancer."

HOW CAN WE TREAT IT?

Neurological deficits and progressive deterioration of brain function in patients with GBM are the result of space-occupying tumor growth and peritumoral swelling. Deterioration not specifically caused by tumor enlargement is often attributable to hemorrhage into the tumor, hydrocephalus, hyponatremic edema, hypertension, seizures, fever, or radiotherapy.⁵

Surgical intervention quickly reduces tumor bulk and the secondary effects associated with the tumor mass, such as hydroceph- alus and edema.⁵ Surgery is generally followed by radiotherapy, which usually results in prolonged survival rates.⁶

"There is no question in my mind that resection can't result in cure in patients with this disease. Some patients with GBM are, indeed, being cured," Friedman asserted. "These patients show no symptoms when seen 5 to 11 years following surgery. We have seen patients considered cured as a result of surgery, as have other major cancer centers across the country," he stressed.

"There are many reasons why these patients do better than others. One reason is the genetic composition of the patient's tumor," Friedman continued. "But in terms of surgery, a patient who undergoes a major resection is going to survive longer and have a better quality of life than a patient who does not have surgical intervention. By major resection, I mean a near-gross total removal of tumor mass close to 98% or better. Patients who receive this level of resection are unequivocally going to live longer with a better quality of life compared with patients who receive suboptimal or a lesser degree of resection."

Friedman conceded that such aggressive resection is not possible in most patients. "You don't want a surgeon in quest of cure to induce a surgically acquired neurological deficit [in an attempt to completely remove the tumor]. A surgically induced deficit is not an appropriate outcome in GBM," said Friedman. "The surgeon should consider what quality-of-life trade-offs might result from the initial procedure."

Because glioblastomas infiltrate the surrounding normal tissue-often by many centimeters from the focus of the primary lesion-radiotherapy is necessary. Brain tissue is not very tolerant of high radiation doses, and this becomes the limiting factor in providing complete cure or even control of tumor spread.⁵ Doses of up to 60 Gy have been used and efforts have been made to increase the levels of radiation used to treat glioblastoma by implanting radio- active seeds in the tumor, which can provide an additional 60 Gy of radiotherapy.⁶ In addition to brachytherapy, radiosensitizing agents have been used with involved-field radiotherapy, but none of these techniques has significantly improved survival.⁶

Nevertheless, radiotherapy is currently the single most effective means of treating GBM. "Virtually every study that has been done is unequivocal in demonstrating that surgery followed by radiotherapy produces results that are superior to therapy using surgery or radiation alone," said Friedman. "There is no question that the addition of radiotherapy to surgery increases the duration and the quality of survival. Again, this combination is not curative, but patients do live longer with a better quality of life."

Radiotherapy might be contraindicated in some patient subsets. "For example, radiotherapy in patients with anaplastic oligodendroglioma probably should be avoided," Friedman said. "We also try to avoid the use of radiotherapy in children younger than 6 years because of the potentially devastating effects radiation to the brain may have on intellectual development. The use of radiotherapy in the very elderly is another area of caution. These elderly patients would probably do just as well without radiotherapy," said Friedman.

ADJUNCTIVE CHEMOTHERAPY

Because most tumors are only partly resectable or even nonresectable because of their location within the cranium and because most are only partially responsive to radiotherapy, chemotherapy may need to be added into the treatment protocol. No consensus of opinion has been established about the routine use of chemo- therapy as an adjunct to radiotherapy; however, chemotherapy may offer an advantage in reaching distant tumor cells, irrespective of their location within the CNS.⁵

Whereas no significant improvements in survival rates have been reported with use of a single agent, significant increases in patient survival have been seen with multi-agent chemotherapy. Lisa M. DeAngelis, MD, chair of the Department of Neurology at Sloan-Kettering Cancer Center in New York, noted in a review published in the New England Journal of Medicine in 2006 that adjunctive multi-agent chemotherapy was consistently associated with an increase in long-term survival irrespective of age (up to 65 years), symptom duration, performance parameters, and histological tumor characteristics.

Advances in chemotherapy research have resulted in temozolomide (Temodar), an oral alkylating compound shown to have anti- tumor activity even as a single agent. When temozolomide is administered (eg, 75 mg/m²/d for up to 7 weeks), the DNA-repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT) is depleted. This enzyme depletion is significant because reduced levels of MGMT in tumor tissue are related to longer survival rates in patients with GBM.⁷ A study by Stupp and colleagues⁷ demonstrated that survival was prolonged by a median of 2.5 months for patients with newly diagnosed GBM receiving radiotherapy and temozolomide, compared with patients receiving radiotherapy alone. This amounted to a relative risk reduction in mortality of 37%.

"Temozolomide has become the standard treatment for palliation in GBM. In subsets of patients-in particular, those who have low MGMT-it produced 2-year survival rates as high as 46%. The bottom line, however, is that you are not going to cure patients in any appreciable number with a malignancy as aggressive as GBM using a single agent," said Friedman. "Keeping this in mind, temozolomide can be viewed as a strong foundation upon which to build a treatment base, but for it to be considered a standard of care in the community is not realistic. By looking at temozolomide this way, you are essentially saying that from day 1, you are simply putting your patients on palliative care."

The way to get around this, according to Friedman, is to get patients into clinical trials so that they can be exposed to newer agents. As an example, Friedman mentioned use of bevacizumab (Avastin) plus CPT-11, which he said is associated with a 60% to 65% response rate in recurrent GBM with a 6-month survival rate of about 43%. "In comparison, the 6-month survival rate for patients taking temozolomide for recurrent GBM is only 21%," said Friedman.

He is currently involved in clinical trials of bevacizumab and CPT-11 and noted that although the combination seems promising, it is unknown which one is the more potent agent. Nevertheless, Friedman named bevacizumab as one of the more promising investigational chemotherapeutic agents for GBM.

GENETIC TARGETS

Some of the underlying genetic abnormalities associated with GBM include overexpression of the epidermal growth factor receptor (EGFR) gene and its most common deletion mutant variant III (EGFRvIII).⁸ Tyrosine kinase inhibitors have been used to block the ligand-activated tyrosine kinase activity of EGFR. Some tumors have been found to respond to this genetic attack, according to Friedman.

EGFR kinase inhibitors alone or in combination with other agents such as rapamycin are expected to be beneficial in selected patients, explained Friedman. Only 10% to 20% of patients with GBM reportedly responded to EGFR kinase inhibitors, though.⁹ Loss of expression of tumor suppressor gene PTEN and its protein phenotype is thought to produce cellular resistance to EGFR kinase inhibitor therapy in GBM.

Reduced sensitivity to EGFR kinase inhibitors in patients with GBM, therefore, has been linked to tumor coexpression of EGFRvIII and PTEN.⁹ The identification of this genetic and phenotypic relationship is an important step in the development of a tumor-specific treatment for GBM, according to Friedman.

"Whether these GBM tumors are EGRFvIII-positive or PTEN wild type-the latter of which augurs a particularly good response to erlotinib [Tarceva]-or whether the tumor response is linked to other molecular profiles, we will begin to unravel the molecular subsets that will predict a better outcome," Friedman said. He added that "once patients with GBM are treated with multi-modality overlapping therapies, we will begin to see a desperately needed increase in the cure and survival rates."