“We developed a strategy to successfully shield the marrow and blood cells and thus patients can now get this drug combination with benzylguanine and temozolomide while the marrow and blood cells are protected and shielded,” Dr. Hans-Peter Kiem from Fred Hutchinson Cancer Research Center in Seattle told Reuters Health by email.

“MGMT (methylguanine methyltransferase) in the tumor will inactivate the chemotherapy and thus make the tumor insensitive to chemotherapy,” Dr. Kiem explained. “We can reverse this by disabling MGMT and making the tumor again sensitive to temozolomide using a drug called benzylguanine. Unfortunately disabling MGMT in blood and marrow cells makes them also more sensitive to temozolomide causing low blood counts and preventing the use of this approach.”

In an effort to protect blood cells from the benzylguanine-temozolomide combination, Dr. Kiem and colleagues transplanted autologous gene-modified CD34+ cells into seven patients with newly diagnosed MGMT promoter unmethylated glioblastoma who had already received >50% surgical resection followed by radiation therapy.

Once they recovered from the stem cell transplant, patients received between two and nine cycles of adjuvant benzylguanine-temozolomide at or above the previously established maximum tolerated dose of temozolomide.

Five of the seven patients experienced myelosuppression following chemotherapy, the researcher report in the Journal of Clinical Investigation, online August 8.

But by 100 days after transplantation, only one patient had significant chemotherapy-associated myelosuppression, and this patient displayed little to no gene-modified cells in circulation at the time of chemotherapy.

In the four patients with durable gene marking throughout chemotherapy, there was a gradual decline in circulating gene-modified peripheral blood cell levels immediately following discontinuation of chemotherapy. The researchers say this suggests a potential disadvantage for gene-modified stem cells in the absence of chemoselective pressure.

One patient experienced a partial response, and six of seven patients experienced progressive disease while on chemotherapy, with a median progression-free survival of nine months. Five of these patients had demonstrated a best response of stable disease, according to the report.

Median overall survival was 20 months, with all seven patients living at one year from diagnosis. Three of seven patients were alive at two years, a significant improvement compared to similar historical patients receiving radiation therapy followed by adjuvant temozolomide. Moreover, all seven patients surpassed the median survival for patients in the same recursive partitioning analysis (RPA) class.

All patients also demonstrated greater average days gained and prevention of radial tumor growth per milligram of temozolomide administered compared with matched controls, and this was sustained for the duration of the treatment course.

As for the cost of treatment, Dr. Kiem said, “I don’t think the cost will be higher than other experimental drug therapies currently being pursued — the main cost is the genetic modification and protection of the blood cells and this is a one-time procedure.”

“This is indeed an interesting strategy especially for those patients who develop temozolomide resistance and are more likely to have severe myelosuppression as an off-target effect of (benzylguanine),” Dr. Rajiv Khanna from Royal Brisbane Hospital in Herston, Queensland, Australia, told Reuters Health by email. “Although the results are quite promising, the cohort size to too small to make any firm conclusion.”

Dr. Khanna, who has investigated other treatments for glioblastoma but was not involved in this study, added, “Immune-based therapies are emerging as powerful tool for the treatment of glioblastoma multiforme (GBM) patients. In particular, T cell therapies targeting GBM-associated antigens have provided promising results and should be considered in combination with gene therapy approach developed by these authors.”

“While lot more work will be required to provide a firm evidence for the benefit of genetically modified stem cell transplantation, this study provides an important platform for the application of this strategy for other cancers (including brain) where alkylating agent chemotherapy is a potential option,” Dr. Khanna concluded.

Source

Patients randomized to conventional treatment with radiation therapy and temozolomide (Temodar) had a median overall survival (OS) of 16.6 months, whereas patients who received radiation and dose-dense temozolomide had a median survival of 14.9 months.

Median progression-free survival (PFS) was about a month longer with the dose-dense regimen, but the difference did not reach statistical significance, reported Mark R. Gilbert, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues online in the Journal of Clinical Oncology.

“This study did not demonstrate improved efficacy for dose-dense temozolomide for newly diagnosed glioblastoma multiforme, regardless of [MGMT] methylation status,” the authors concluded. “However, it did confirm the prognostic significance of MGMT (methylguanine-DNA methyltransferase) methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.”

A substudy within the trial, also published in the journal, showed that dose-dense temozolomide was associated with more symptoms and with greater deterioration of global health and motor function as compared with the standard regimen.

The current standard of care for glioblastoma is surgery or radiotherapy with concurrent temozolomide (chemoradiation). However, prognosis remains poor, as only about a fourth of patients survive to 2 years, the authors noted.

As part of the international cooperative-group trial that established the standard for therapy, investigators obtained tumor specimens from a subset of patients to examine changes in the promoter region of MGMT DNA repair gene. Research has shown that the enzyme has a major mechanistic role in glioblastoma’s ability to develop resistance to alkylating agents, which include temozolomide.

Examination of the tumor specimens showed that methylation-mediated silencing of the promoter region of MGMT was associated with significant improvement in OS, suggesting that modulation of enzymatic activity might improve sensitivity and response to alkylating agents.

Dose-dense temozolomide schedules have been evaluated in patients with recurrent disease and in nonrandomized studies, which showed efficacy and compared favorably with that of the standard regimen without causing additional toxicity. Schedules of 7 days on/7-days-off and 21- to 28-day cycles achieved depletion of MGMT activity. Standard therapy with temozolomide is to administer the drug on five of every 28 days.

Gilbert and colleagues hypothesized that prolonged exposure to temozolomide would improve survival in newly diagnosed glioblastoma. To test the hypothesis, investigators in Europe and North American randomized 833 patients to standard-regimen temozolomide plus radiation therapy or to dose-dense temozolomide and radiotherapy.

The primary endpoint was OS; PFS and toxicity were key secondary endpoints. Median duration of follow-up was 31.5 months.

The 1.7-month difference in OS translated into a hazard ratio of 1.03, which was not statistically significant (P=0.63). The patients randomized to standard temozolomide had a median PFS of 5.5 months versus 6.7 months for the dose-dense group (HR 0.87, P=0.06).

Data on tumor methylation status was available for 762 patients. Investigators found a significant difference in survival for patients with methylated MGMT (21.2 months) versus those with unmethylated promoter gene (14 months, HR 0.58, 95% CI 0.48-0.69, P<0.001). Median PFS was 8.7 months with methylated tumors and 5.7 months with unmethylated tumors (HR 0.61, 95% CI 0.52-0.73, P<0.001).

The dose-dense regimen was associated with increased grade ≥3 toxicity (34% versus 53%, P<0.001), primarily lymphopenia and fatigue.

Dose-dense temozolomide also had a greater adverse impact on neurocognitive function, symptoms, and quality of life, Terri S. Armstrong, PhD, of the University of Texas Health Science Center at Houston, and colleagues reported in the second article.

Investigators used validated assessment instruments to evaluate the outcomes in 182 patients at baseline and after each of the planned six cycles of therapy. Baseline scores related to neurocognitive and physical function were associated with both OS and PFS. The change in the net clinical benefit (results of all tests) from baseline to cycle one also was associated with overall survival and PFS.

Patients in the dose-dense arm had greater deterioration in all components of net clinical benefit from baseline to cycle four in global health and motor function scores, overall symptom burden, overall symptom interference, and activity related symptom interference. Neurocognitive function did not differ between the groups.

“Although future trials incorporating the net clinical benefit measures are needed to validate these findings, our results strongly support making the net clinical benefit measures a component of brain tumor clinical trials,” Armstrong’s group concluded. “These net clinical benefit measures can potentially be used for stratification and also provide a dimension of treatment for efficacy that is not adequately determined by traditional measures.”

1. Assistant Professor, Departments of Radiation Oncology and Pathology; 2. Professor and Deputy Chair, Department of Neuro-oncology, University of Texas MD Anderson Cancer Center

The purpose of this article is to review the current treatment options for patients with glioblastoma (GBM). The current standard of care involves maximal safe surgical resection followed by concurrent chemotherapy with radiation followed by adjuvant chemotherapy. Although level 1 evidence supports the use of this treatment, GBM remains incurable and most patients will succumb to the disease within two years of diagnosis. The need for better treatments has led to the development of numerous experimental agents that are currently in various phases of pre-clinical and clinical application. The new treatment approaches provide hope that significant treatment advances are likely, but will require a collaborative effort between laboratory-based and clinical investigators.

Demographics

GBM is the most common and malignant primary brain tumor. While it is more prevalent among older adults, it is a disease that afflicts people of all ages, races, and gender. Most series report a median age in the mid-50s.^1–3 There are no identifiable risk factors or social habits that induce GBM tumorigenesis. There are few cases of familial GBM, but it is a sporadic disease. Patients with certain genetic diseases such as neurofibromatosis, tuberous sclerosis, and Li Fraumeni syndrome have a much higher risk of developing malignant gliomas than the general population.

Survival and Risk Stratification

Most series report that the median survival from the time of diagnosis is approximately one year. The actuarial two-year overall survival is about 5–15%. Even in patients with the most favorable prognostic factors, the likelihood of surviving for any longer than two years is only 25%. The single most important prognostic factor in GBM is patient age. Although age has important implications with regards to issues of patient management (including the greater comorbidities and decreased reserve that preclude aggressive therapy), patient age seems to correlate with differences in tumor biology and pathogenesis. The classic concept of primary (de novo) and secondary GBM have strong associations with age. Typically, older patients are more likely to have primary GBMs, characterized by amplification of the epidermal growth factor receptor (EGFR) gene and a more aggressive clinical course. In these patients, large, debilitating tumors can arise within several months. Secondary GBMs are more often associated with younger patients who frequently have an established history of lower-grade gliomas (grade II–III). These tumors often display protein (p)53 accumulation on tumor sample staining, indicating mutation of the TP53 gene.

The patient’s performance status is another factor. Most studies have correlated a higher performance status with improved prognosis. This may reflect both the patient’s ability to tolerate treatment and the extent of tumor burden in the brain. The extent of resection has also been a statistically significant prognostic factor in some studies; however, this remains somewhat controversial. While a complete resection of the enhancing component of the tumor confers an improved overall survival time, no statistically well-powered randomized trial has been performed. Although the association between extent of resection and outcome has been shown in several series, this may reflect differences in tumor biology or patient performance status rather than the impact of tumor removal. The data supporting a sub-total resection over a biopsy are quite limited and inconclusive.

The evaluation of prognostic factors is important when considering treatment options for individual patients and critical when evaluating the efficacy of treatment regimens tested in clinical trials. Selection of patients with excellent prognosis may inappropriately skew the results so, compared with a ‘typical’ patient population, the new treatment appears (erroneously) effective. The impact of prognostic factors is so critical to the evaluation of new therapies that the Radiation Therapy and Oncology Group (RTOG) devised the recursive partitioning analysis (RPA) for malignant gliomas. This validated analysis was able to define six distinct groups of patients with malignant gliomas on the basis of tumor histology and additional clinical factors. The RTOG RPA⁴ was recently simplified for GBM⁵ and shares features similar to the European Organisation for Research and Treatment of Cancer (EORTC) classification schema.

Maximal Resection

Although not proved in a randomized phase III study, several studies do support maximal, safe surgical resection. For example, data from the University of Texas MD Anderson Cancer Center indicate that >98% resection of the enhancing component of the tumor results in the best outcome.⁷ Interestingly, complete resection of the non-enhancing component does not result in a significant difference in survival and may increase post-operative morbidity.

Intra-operative Treatments

Local treatments can also be administered at the time of the surgical resection. For example, a biodegradeable polymer containing carmustine (BCNU) has been approved for placement along the walls of the tumor resection cavity for both newly diagnosed and recurrent GBM. The wafer will dissolve over two to three weeks, slowly releasing the carmustine into the cavity walls. Radioactive seed implants are also placed at the time of surgery; however, phase III studies do not demonstrate any survival benefit when this technique is used in combination with standard external-beam radiotherapy (EBRT).

A new brachytherapy device—a balloon catheter system that is inflated with radioactive liquid iodine—has been developed and is currently undergoing testing in clinical trials. The balloon conforms to the shape of the cavity and may deliver a more uniform dose of radiation to the tumor bed. No proof of improved efficacy has been reported. Finally, convection-enhanced delivery is undergoing extensive evaluation. Catheter placement into the brain parenchyma surrounding the tumor cavity followed by continuous delivery of treatment under pressure promotes diffusion of the treatment into areas of the tumor that were previously not reachable by systemic delivery because of the blood–brain barrier. Targeted agents such as antibody fragments and gene therapies are currently being studied using this delivery modality.

Post-operative Imaging

For an accurate evaluation of resection, a post-operative magnetic resonance imaging (MRI) scan is best obtained within 72 hours of surgery and preferably within 48 hours.⁸ This avoids misinterpreting post-operative changes such as edema and hyperemia at the resection margin. These can be mistaken for residual tumor.

Radiation Therapy

RT has long been the mainstay of adjuvant treatment in GBM, with well-documented improvement of patient survival times from approximately 14 weeks with surgery and supportive care to 36 weeks with the addition of EBRT.^9–11 Although radiation has demonstrated efficacy, the dose, fractionation, target delineation, and use of concurrent agents have been part of an ongoing search for improvement. There have been several dose-escalation studies that have failed to reveal a survival advantage in doses above 60Gy. Furthermore, accelerated hyperfractionation, hypofractionation, and the use of Boron neutron capture have all failed to show any benefit. Collectively, from these studies, the standard dosing for GBM emerged as 60Gy at 1.8–2Gy per fraction.

GBM is a difficult disease to treat with radiation because, although it rarely metastasizes outside the central nervous system, it can infiltrate throughout the brain. Autopsy studies consistently show malignant cells that are a significant distance from the primary site.¹² However, despite this fact, more than 80% of tumors recur within the original tumor location. The radiation field remains restricted as studies demonstrated no survival improvement with whole-brain RT, but a higher incidence of treatment-induced brain injury compared with regional radiation. Therefore, the use of radiation is largely to reduce the tumor burden within the brain and to slow the disease process. In keeping with the goal of treating the areas with the highest concentration of tumor, it has been recognized that there are often significant numbers of tumor cells within the T2/fluid-attenuated inversion-recovery (FLAIR) abnormality on MRI.¹³ However, the presence of T2/FLAIR abnormality may be the result of the mass effect created by these tumors, and discriminating areas of tumor from reactive or vasogenic edema may be difficult. As a result, the delineation of treatment volumes remains an area of debate. The RTOG recommends coverage of the whole T2/FLAIR signal with a 2cm margin, and this volume should be treated with 46Gy. The surgical cavity and, if present, residual enhancing tumor is given a 2.5–3cm margin and is boosted to a total dose of 60Gy.

Chemotherapy

Chemotherapy has been extensively evaluated in the treatment of patients with GBM, both as first-line therapy and for patients with recurrent disease. The studies that confirmed the benefit of RT failed to demonstrate any improvement in survival with the addition of nitrosourea chemotherapy (semustine, carmustine). In fact, a large meta-analysis requiring the analysis of over 3,000 patients comparing those who received radiation with chemotherapy with those receiving radiation alone demonstrated only a 6% improvement in the one-year survival rate.¹⁴ Conventional chemotherapy for recurrent disease typically demonstrates a 5–15% objective response rate and a 15–25% six-month progression-free survival (PFS), suggesting that the objective responses are often not durable.

Until recently, no study had provided level 1 evidence of a benefit for chemotherapy in treating patients with GBM. The phase III clinical trial conducted by the EORTC and National Cancer Institute of Canada (NCIC) demonstrated, for the first time, that a chemotherapeutic agent could improve overall survival in GBM patients. In the experimental arm, the addition of TMZ 75mg/mg2 daily, given concurrently with standard radiation (60Gy in 30 fractions), and adjuvant TMZ alone 150–200mg/mg2 daily for six months improved the median survival from 12.1 to 14.6 months, but, more importantly, increased the long-term survivorship (>2 years, actuarial) from 10.4 to 26.5%. The unadjusted hazard ratio for death in the RT–TMZ group was 0.63 (95% confidence interval (CI) 0.52–0.75; p<0.001 by the log-rank test). ¹⁷

Additionally, an analysis was performed on these data comparing patients in the two treatment groups (stratified by prognostic group) and determined by a recursive portioning analysis (RPA). Six distinct prognostic groups have been determined and patients with glioblastoma can be in class III–VI in order of worsening prognosis. Survival with combined RT/TMZ was higher in RPA class III, with a median survival time of 21 months and a 43% two-year survival rate, versus 15 months and 20% for RT alone (p=0.006). In RPA class IV, the survival advantage remained statistically significant, with median survival times of 16 and 13 months, respectively, and two-year survival rates of 28 and 11%, respectively (p=0.0001). In RPA class V, however, the survival advantage of RT/TMZ was of borderline significance (p=0.054).⁶

Overall, there was a statistically significant improvement in both median survival and two-year survival rate for patients with methylated MGMT.¹⁹ This suggests that MGMT methylation is a positive prognostic factor. Furthermore, those patients with promoter methylation of the MGMT gene who were treated with chemoradiation had an improved two-year survival rate compared with those patients with methylated MGMT promoter who received only radiation, suggesting that MGMT promoter methylation is also predictive of response to TMZ chemotherapy. Among those patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with TMZ and RT; their median survival was

21.7 months (95% CI 17.4–30.4) compared with 15.3 months (95% CI 13.0–20.9) among those who were assigned to RT only (p=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups.¹⁹

The successor trial to the EORTC trial is currently accruing patients. This is an international collaborative effort involving the RTOG, the EORTC, and the North Central Cancer Treatment Group (NCCTG). The protocol, RTOG 05-25, enrols patients with newly diagnosed GBM. All patients receive conventional chemoradiation, and are then randomized to receive either standard-dose adjuvant TMZ of six to 12 months or TMZ using a dose-dense schedule of 100mg/m2 on days one to 21 of a 28-day cycle. Stratification is performed factoring in both RPA prognostic class and MGMT gene promoter status. The latter stratification factor has mandated the submission of tumor tissue paraffin blocks for all patients. This material will provide the ability to perform additional molecular profiling that may enhance the understanding of glioma biology and aid discovery of new therapeutic targets.

Special Considerations

High-risk Patients

High-risk patients are defined as those with a poor performance status, large tumor burden that causes neurological dysfunction, or significant comorbid conditions that increase the risk of requiring brain tumor therapies. These factors often have a significant impact on prognosis. As high-risk patients have a short life expectancy, the use of tri-modality therapy (surgical resection, radiation, and chemotherapy) must be weighed against the potential toxicities, compromises, and quality of life. Often, these patients have extensive radiographic evidence of disease and the upfront surgical intervention is biopsy alone for diagnostic purposes. A hypofractionated radiotherapy regimen can be used in this setting (50Gy in 20 fractions), which trades off the risk of late toxicity with a shorter overall treatment time (six weeks instead of four) with no increased toxicity or apparent impact on survival.²⁰ Treatment of elderly patients (usually older than 70 years) with GBM remains controversial. Studies have demonstrated similar survival rates using either chemotherapy or radiation alone, although an adequately powered phase III study has not been reported. Recent data from the EORTC show that elderly patients with a Karnofsky Performance Score (KPS) >70 achieved a modest improvement in median overall survival—29.1 versus 16.9 weeks—with no detriment to their quality of life.²¹ Furthermore, retrospective data from the University of Texas MD Anderson Cancer Center showed that RPA class V and VI patients who received RT had a 20% radiographic response rate and an approximately 90-week overall survival.²² Randomized studies are planned to formally compare radiation with chemotherapy and chemoradiation with radiation alone in this age group. Typically, the decision to use radiation in patients with poor performance status and advanced age should take into account the patient’s and family’s wishes, expectations, and social situation. The logistics and time commitment of fractionated RT can compromise the quality of remaining life of the patient. The use of TMZ is frequently given in this palliative setting, although there are no phase III data to support this application. In many situations, supportive care alone can be used, and is appropriate if the patient and family decide to not pursue aggressive treatment.

Brainstem Glioma

Frequently, the diagnosis of brainstem glioma is made empirically via imaging studies, without the benefit of an actual tissue-based diagnosis. These lesions are diffuse and often show T2/FLAIR hyperintensity and/or contrast enhancement on MRI. For lesions in this location, the standard treatment is RT alone. Because the actual grade of the tumor is unknown, the brainstem should be treated to its tolerance dose. The gross tumor volume is defined by the T2/FLAIR and enhancement abnormalities. Since these tumors spread along white matter tracts, a radial margin of 0.5cm and a longitudinal margin of 2m is treated to within the tolerance dose of the brainstem (54Gy in 28 fractions). As described above, patients do not typically undergo a biopsy. However, despite the absence of phase III data to support the use of concurrent systemic or radiosensitizing agents, use of chemoradiation is increasing for the treatment of brainstem gliomas in adults.

Recurrent Tumors

Patients with GBM nearly always develop recurrent or progressive tumor growth. However, unlike patients with newly diagnosed disease, no level 1 evidence exists to guide therapy; therefore, treatment options and decisions are often determined by the specific clinical situation and treatment availability.

Re-operation

Most series report that approximately 20–40% of patients with recurrent GBM undergo re-resection of tumor at the time of recurrence. This varies by center and treatment provider. No formal guidelines exist to assist in the decision; however, patients with a local recurrence in non-eloquent brain regions are more likely to undergo a repeat tumor resection. This procedure can relieve mass effect and resolve issues related to increased intracranial pressure. In addition, the tissue can be analyzed to distinguish between treatment effect (necrosis) and active progressive tumor. Furthermore, the newly established tumor cavity permits use of a local therapy strategy such as placement of BCNU-containing biodegradable polymers or an intra­cavitary balloon for subsequent local radiation using brachytherapy.

Chemotherapy

Chemotherapy regimens are commonly used to treat patients with recurrent GBM. To date, no regimen has been proved in terms of efficacy by randomized clinical trials in order to become the established standard of care. A wide spectrum of therapeutic regimens have been tested, including single-agent cytotoxic chemotherapies, such as irinotecan (CPT-11), or combination regimens, such as irinotecan with TMZ. Objective response rates in recurrent GBM to cytotoxic regimens remain low (5–15%). More recently, six-month PFS rate has been used as a measure of efficacy, based on a statistical analysis that set a six-month PFS rate of 15% or less as an indication of low activity.²³

Re-irradiation

Due to the success of TMZ, especially in its creation of more long-term survivors, the use of re-irradiation will become more common in clinical practice. This also creates an impetus for more careful delivery of radiation in the definitive setting. Stereotactic radiosurgery/RT can be used for small volumes of recurrence that appear within a short period of time, close to or within the previous high-dose region.²⁴ Specifically, tumors <4cm can be treated with stereotactic radiosurgery using 12–20Gy in a single fraction. For tumors >4cm, fractionated 3D-conformal or intensity-modulated radiation therapy (IMRT) can be used, but the dose and timing must be tailored to prevent radiation necrosis. Doses of 30–50Gy can be used, depending on the previous dose received by the volume. For tumors that recur within the 60Gy volume, 12–15 months are required between radiation courses. Tumors in the 50Gy region should have a period of 12 months between courses. Lastly, tumors outside of significant dose volumes can be treated three to six months after completion of the initial course.

Novel Agents

Patients with recurrent GBM often gain only minimal or modest benefit from conventional treatments. Therefore, there has been great interest in developing new treatment regimens for this group of patients. A wide variety of traditional cytotoxic chemotherapy agents such as cisplatin, carboplatin, procarbazine, and irinotecan have been tested. Most studies demonstrate only modest benefit, with objective response rates reported in the 5–15% range, and response is often not durable. More recently, signal transduction­modulating agents have been evaluated. As outlined in Table 3, a large number of new drugs have been synthesized with a limited number of specific pathway targets. To date, response to these drugs as single-agent therapy has been limited; however, combinations with cytotoxic therapies may prove to be more beneficial. Combinations of signal transduction modulators have recently been moved into clinical trials. Careful phase I testing has revealed that these strategies may have overlapping toxicities that were unanticipated from the general low toxicity of treatment with single agents. Currently, the efficacy of combination regimens using signal transduction modulators has not been determined, but is an area of active investigation.

Conclusions

Although the prognosis for patients with GBM remains guarded, there have been some recent advances in treatment that clearly demonstrate that multimodality therapy can improve outcome. The standard of care is to maximally debulk the tumor and follow this with concurrent chemotherapy and EBRT. This is followed by additional adjuvant chemotherapy. Despite this new standard of care, better treatments are needed. Currently, there are active investigations of signal transduction modulators along with extensive studies of tumor molecular profiles. These parallel investigations will ultimately result in individualized patient treatment. In this scenario, laboratory testing of tumor samples including molecular profiling will determine the optimal regimen, analogous to the use of tratuzumab in human epidermal growth factor (HER)2-positive breast cancer. The collaboration of laboratory scientists and clinical investigators holds great promise for future advances in treatment.

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James B Powell Jr Professor of Neuro-oncology, Dukes University Medical Center

The treatment of patients with glioblastoma multiforme (GBM) is conventionally considered to be a palliative venture with no hope of cure. Traditionally, patients are treated with maximal surgical resection based on the premise that, although surgery is not a curative procedure, a major resection provides for a longer survival and better quality of life.¹ Radiotherapy increases the duration of survival, but again is not a curative intervention.² The role of chemotherapy, specifically focusing on a foundation of chloroethylating agents such as carmustine (BCNU) or lomustine (CCNU), has been controversial with an equal number of clinicians arguing in favor of or against this treatment. Meta-analysis makes it clear that there is a small increase in median survival associated with the addition of these agents, but a consensus was never reached regarding their use.³

Unfortunately, the underlying assumption of virtually all clinicians that GBM is not a curable tumor led to a wide spectrum of interventions utilized in the community to treat these patients. Many patients received a biopsy rather than a major resection of their tumor. Despite the lack of evidence supporting whole-brain versus focal radiotherapy, some patients received (or still receive) whole-brain radiotherapy with the associated increased morbidity. Finally, community and academic physicians chose to not use chemotherapy without a firm foundation of data to support withholding it.

A positive step forward started with the synthesis and evaluation of temozolomide and subsequent phase I and II trials with this methylating agent in the UK. Temozolomide was shown to have activity in phase I trials in two patient populations: those with malignant glioma or those with melanoma.⁴ Subsequent phase II trials in the UK confirmed this activity,⁵ leading Schering Plough to license the drug for studies in the US. Following phase I trials in adults and children, a pivotal registration trial in patients with GBM, and also anaplastic astrocytoma in a separate

Henry S Friedman, MD, is the James B Powell Jr Professor of Neuro-oncology at Duke University Medical Center. Dr Friedman

serves as the Deputy Director of The Preston Robert Tisch Brain

Tumor Center at Duke. He is internationally recognized for his

work as an educator, clinician, and laboratory/clinical investigator

in both pediatric and adult brain and spinal-cord tumors. He has

published over 350 articles in peer-reviewed professional journals.

He received his MD from Upstate Medical Center in Syracuse,

New York, in May 1977 and stayed at that institution for pediatric

and pediatric hematology-oncology training. He trained in neuro-oncology at Duke University

Medical Center, and joined the faculty at that institution in 1983.

trial—as well as a trial of newly diagnosed patients with GBM with residual disease following initial surgical intervention or biopsy intervention—were initiated. The first published study by Friedman et al.⁶ demonstrated the profound activity of temozolomide in patients with newly diagnosed GBM with a response rate exceeding 50%. Although the registration trial for patients with first-relapse GBM demonstrated a near tripling of the six-month progression-free survival, concerns voiced by the US Food and Drug Administration (FDA) regarding this as a legitimate end-point prevented the approval of temozolomide for this indication.⁷ However, the one-arm study evaluating temozolomide in the treatment of patients with first-relapse anaplastic astrocytoma led to an accelerated approval for this agent.⁸

Roger Stupp took the next step forward by building on the results of the prior studies of temozolomide. A one-arm trial was initiated of 65

We now routinely include Bevacizumab and irinotecan in the treatment of all newly diagnosed patients with glioblastoma multiforme who are not enrolled on clinical trials.

patients who received surgery then radiation with daily temozolomide, followed by six cycles of traditional five-days-a-month temozolomide.⁹ These results showed a provocative survival curve leading to a randomized phase III trial in patients with newly diagnosed GBM. The results confirmed the benefit of temozolomide, which produced a modest increase in survival for patients receiving this agent.¹⁰ Overnight, temozolomide became the global standard of care. Ironically, an agent producing a very similar increase in survival—notably Gliadel wafers, which release BCNU into a tumor cavity following their implantation— has not been as universally accepted.¹¹ Although this may have initially reflected concerns with toxicity—due to a lack of appreciation of the need for a watertight dural seal following placement of these wafers— and the initially unfavorable cost, at least in the US, it is now clear that both of these problems have been addressed and the use of this agent appears to be increasing.

The problem that we currently face in the field is the continued belief that patients with GBM will die, and therefore our efforts are merely

palliative. Accordingly, patients are treated routinely in the community with surgery followed by radiation and temozolomide, followed by temozolomide with virtually no hope of long-term survival. It is absolutely ludicrous to believe that any malignancy, particularly one as aggressive as GBM, can be cured with single-agent chemotherapy. Nevertheless, this standard of care persists because there is a concern that there are no other active agents, and the belief that only patients on clinical trials should receive agents that are not approved by the FDA to counter a specific malignancy. Although the community standard of care in the US for oncology patients is to utilize commercially available agents in an off-label setting when data support their use, in many academic neuro­oncology programs there is major resistance to this approach. This problem can be dealt with in two ways. The first is to design clinical trials using multiple agents in the treatment of GBM. The study by La Rocca et al. is a step in the right direction since it evaluates the use of surgery with placement of Gliadel wafers followed by radiation and temozolomide, followed by temozolomide as a single agent in the treatment of patients with newly diagnosed GBM.¹²

Patients not on a clinical trial can also be treated with off-label commercially available agents, particularly if other studies will evaluate these agents in formal clinical trials, so we are not slowing the progress of the field, but offering patients hope who are not on a trial. An example of this would be the use of Bevacizumab, which in recent studies in combination with irinotecan has been shown to have an extraordinary response rate and duration of response.^13,14 Although phase III trials that evaluate this agent in newly diagnosed patients will be forthcoming, there is no reason why patients who are not protocol-eligible cannot receive this as part of their standard of care. We follow this strategy of using off-label commercially available drugs at Duke and, between 2003 and 2006, 85 patients were treated with surgery, Gliadel wafers (if anatomically appropriate), and radiation therapy with concomitant temozolomide, followed by a rotation of temozolomide, CCNU, and irinotecan. These results are promising and prevent the all too frequent occurrence that only patients on clinical trials are offered optimistic therapy.¹⁵ We now routinely include Bevacizumab and irinotecan in the treatment of all newly diagnosed patients with GBM who are not enrolled on clinical trials.

An additional concern that has arisen following the universal acceptance of temozolomide has been the role of O6-methylguanine-DNA methyltransferase (MGMT)—also known as O6-alkylguanine DNA alkyltransferase—in making decisions regarding the use of temozolomide. A series of clinical studies have clearly demonstrated the role of this protein in predicting response to temozolomide. Friedman et al.⁶ showed this first in the upfront study of patients with newly diagnosed GBM. Roger Stupp built on this with subsequent trials further defining the relationship between MGMT and temozolomide. Unfortunately, it is not an all or nothing relationship, particularly when

Patients with glioblastoma multiforme are not universally incurable with an ever-increasing, albeit small, fraction of patients who appear to survive the disease.

using the promoter methylation assay. It is clear that any recommendations to use or not use temozolomide based on this assay are inappropriate. Maxwell et al.¹⁶ clearly demonstrated that even in a situation where the methylation assay actually showed a lack of methylation of the promoter, there is still a population of cells that do not stain for MGMT and, therefore, are likely to be sensitive to temozolomide. The appropriate recommendation when the MGMT promoter is not methylated is not to withhold temozolomide, but to use it while including additional agents that will not be susceptible to this protein. Of course, we argue that additional agents should always be used, and never rely on temozolomide alone as a single agent.

Patients with GBM are not universally incurable, with an ever-increasing, albeit small, fraction of patients who appear to survive the disease. The classical wisdom of utilizing multiple chemotherapeutic agents with non-overlapping toxicity and independent mechanisms of action unequivocally is producing an ever-increasing cohort of patients for whom GBM is not a terminal event. Reliance on a single agent, whether temozolomide or anything else, is nihilistic, inappropriate, and clearly going to be unsuccessful.

1               Lacroix M, Abi-Said D, Fourney DR, et al., A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival, J Neurosurg, 2001;95:190–98.

2               Fine HA, The basis for current treatment recommendations for malignant gliomas, J Neurooncol, 1994;20:111–20.

3               Stewart LA, Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials, Lancet, 2002;359:1011–18.

4               Newlands ES, Blackledge GR, Slack JA, et al., Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856), Br J Cancer, 1992;65:287–91.

5               O’Reilly SM, Newlands ES, Glaser MG, et al., Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours, Eur J Cancer, 1993;29A:940–42

6               Friedman HS, McLendon RE, Kerby T, et al., DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma, J Clin Oncol, 1998;16:3851–7.

7               Yung WK, Albright RE, Olson J, et al., A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse, Br J Cancer, 2000;83:588–93.

1               Yung WK, Prados MD, Yaya-Tur R, et al., Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse, Temodal Brain Tumor Group, J Clin Oncol, 1999;17:2762–71.

2               Stupp R, Dietrich PY, Ostermann Kraljevic S, et al., Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide, J Clin Oncol, 2002;20: 1375–82.

3               Stupp R, Mason WP, van den Bent MJ, et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N Engl J Med, 2005;352:987–96.

4               Westphal M, Hilt DC, Bortey E, et al., A phase III trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma, Neuro Oncol, 2003;5:79–88.

5               La Rocca RV, Hodes J, Villanueva WG, et al., A phase II study of radiation with concomitant and then sequential temozolomide (TMZ) in patients with newly diagnosed supratentorial high-grade malignant glioma who have undergone surgery with carmustine (BCNU) wafer insertion, Society of Neuro-Oncology, Orlando, Florida, 2006;8(4):445, Abstract TA-28.

1. Vredenburgh JJ, Desjardins A, Herndon JE II, et al., Bevacizumab and Irinotecan: an active regimen against recurrent glioblastoma multiforme, J Clin Oncol, 2007, in press.
2. Vredenburgh JJ, Desjardins A, Herndon JE II, et al., Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma, Clin Cancer Res, 2007;13:1253–9.
3. Affronti ML, Heery C, Rich J, et al., Overall survival of primary glioblastoma (GBM) patients (pts) receiving Carmustine (BCNU) wafers followed by radiation (RT) and concurrent Temozolomide (TMZ) plus rotational multi-agent chemotherapy, American Society of Clinical Oncology, Chicago, Illinois, 2007
4. Maxwell JA, Johnson SP, Quinn JA, et al., Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma, Mol Cancer Ther, 2006;5:2531–9.

“It is from this group doubtless that the generally unfavorable impression regarding gliomas as a whole has been gained. It is not only the largest single group in the series…but at the same time is one of the most malignant…In the five unoperated cases, the average duration of life from the onset of symptoms was only three months, which speaks well on the whole for the average survival period of twelve months for those surgically treated.

Since their seminal work, the median survival of 12 months has not changed markedly. Both data from the 1960’sand current data confirm that the extent of surgical resection is an important prognostic factor. However, as Bailey and Cushing observed, GBMs have “infiltrating propensities, and…when enucleation is attempted, the growth is found at the depth to spread into and merge with the normal cerebral tissue without recognizable demarcation. In prior eras, radical surgical excisions, including removal of the entire cerebral hemisphere containing the tumor,⁵ were occasionally attempted, yet patients who survived the hemispherectomy died of recurrent tumor,⁶ clinically proving the importance of the histologic observation that tumor cells invade throughout the brain. In the modern age, brain imaging may disclose macroscopic tumor in the opposite hemisphere (see Figure 1) or even gliomatosis cerebri—literally a brain full of tumor. In the years leading to up to World War II, the German pathologist Scherer, whose scientific discoveries were tainted by his Nazi activities,⁷ described ‘secondary structures’^8,9 that further characterized invasive tumor cells. These structures are ‘secondary’ because they are dependent for their formation on underlying normal brain structures, as opposed to ‘primary’ structures of the tumor such as pseudopalisading necrosis and microvascular proliferation. Examples include perineuronal and perivascular satellitosis (accumulation of tumor cells around neurons and blood vessels), subpial spread, and intrafascicular tracking such as infiltration along corpus callosum and other white matter tracks.

Glioblastoma Multiforme—Past, Present, and Future

Read more: Glioblastoma Multiforme—Past, Present, and Future