M.A. Hayat (ed.)Tumors of the Central Nervous System, Volume 12Tumors of the Central Nervous System1210.1007/978-94-007-7217-5_25

25. Drugs for Primary Brain Tumors: An Update

Lauren Nye¹, Timothy Huyck¹ and Jeffrey Raizer²

(1)

Department of Medicine, Section Hematology/Oncology, Northwestern University, 251 East Huron Street, Galter Suite 3-150, Chicago, IL 60611, USA

(2)

Department of Medicine, Medical Neuro-Oncology, Northwestern University, 710 North Lake Shore Dr. Abbott Hall, Room 1123, Chicago, IL 60611, USA

Jeffrey Raizer

Email: jraizer@nmff.org

Introduction

Historical Overview of Chemotherapy in Maligant Gliomas

Concomitant Chemotherapy and Radiation

Chemotherapeutic Limitations

Chemotherapy for Recurrent Malignant Gliomas

Special Consideration for Anaplastic Oligodendroglioma

Conclusion

References

Abstract

Primary brain tumors are a heterogeneous mix of tumors that can arise from structures within the cranium. This review will focus on tumors of glial origin. The best first approach to a primary brain tumor is maximal safe surgical resection. If the tumor is not amenable to resection, a biopsy is needed for tissue diagnosis. Despite maximal resection of the tumor, there always remains residual disease due to the infiltrative nature of the tumor. This has led to development of various chemotherapeutic regimens which have been developed for use in the neo-adjuvant, adjuvant and recurrent setting. The most significant development of these tumors is for high grade gliomas. Anaplastic astrocytomas and glioblastoma multiforme are frequently diagnosed tumors that continue to have a poor prognosis and short survival. Historically, chemotherapy has been demonstrated to provide a marginal survival benefit in patients with anaplastic astrocytoma and glioblastoma multiforme when used after surgical resection and radiation therapy. Modest improvement in overall survival was initially seen with the use of nitrosurea drugs, such as BCNU and CCNU, as well as some platinum compounds. More recent data suggests the use of temozolomide (TMZ) leads to an improved overall survival when given concurrently with radiation following resection of these aggressive tumors. Data on the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, has also been available and will be presented in the preceding text. Chemotherapeutic agents had a less pivotal role in the setting of low grade astrocytomas and other primary brain tumors.

Introduction

In 2010, an estimated 22,020 new cases of primary brain tumors and other nervous system neoplasms were diagnosed in the United States. These tumors were responsible for approximately 12,140 deaths. The number of newly diagnosed primary brain tumors has been increasing in the last 30 years, a number which is particularly appreciated in the elderly population (Jemal et al. 2010). CNS tumors are associated with a wide range of symptoms and complications such as edema, seizures, endocrinopathy, fatigue, psychiatric disorders, venous thromboembolism all of which can negatively impact quality of life of patients. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, neuro and medical oncologists, neuroradiologists and neuropathologists optimizes the management of these patients. In the recent past there have been a few proven chemotherapeutic agents which have expanded the role of the oncologist in caring for patients with primary brain tumors.

Historical Overview of Chemotherapy in Maligant Gliomas

Malignant gliomas (MGs) account for almost half of all gliomas. The most common MGs are glioblastoma (GBMs), or rarely gliosarcomas, which account for 60 % of these tumors. Anaplastic gliomas (AG) are composed of astrocytomas (AAs: 10–15 %), anaplastic oligodendrogliomas (AOs: 8–10 %) and anaplastic oligoastrocytomas (AOAs: 8–10 %) (Stern and Raizer 2006). The most common form of initial treatment for MGs is surgical intervention. Indications for surgery include histologic diagnosis, reducing tumor burden and alleviating mass effect. External beam fractionated therapy is an appropriate form of treatment for MGs with numerous randomized controlled clinical trials showing a survival benefit for patients receiving surgical resection and irradiation versus resection alone (Walker et al. 1978). Irradiation is typically performed over 6–7 weeks, with patient receiving treatment 5 days per week (18–200 cGy fractions to a total dose of 6,000–6,140 cGy). In the 1960s and 1970s, surgical resection and postoperative external beam radiation therapy were established as the standard treatment approach for patients with GBM and AG (Laperriere et al. 2002).

In the late 1970s, investigators began to evaluate the role of chemotherapy when it became obvious that surgical resection and radiation were not curative. Early trials identified two nitrosurea drugs (CCNU and BCNU) as having a positive effect in treating patients with high-grade gliomas. In the late 1970s the first large scale multi-center trial for brain cancer was BTCG 7201, Walker et al. (1980) looked at the use of nitrosureas in combination with radiotherapy following surgery. Results of this study suggested a trend toward improved survival in the subjects randomized to receive chemotherapy, however the results were not statistically significant. Multiple other studies followed evaluating the role of chemotherapy in conjunction with irradiation, all of which showed either minimal or modest benefit from chemotherapy. The results of these studies were pooled for analysis for three large in meta-analyses.

The first of these meta-analyses was performed by Fine et al. (1993), with a review of 16 randomized trials that included more than 3,000 patients, to compare survival rates of patients that had received radiation therapy and chemotherapy versus radiation alone. The application of chemotherapy was associated with an absolute increase in survival of 10.1 % at 1 year and 8.6 % at 2 years. This improvement translated to a relative increase in overall survival of 23.4 % at 1 year and 52.4 % improvement at 2 years (Fine et al. 1993). A second meta-analysis by Stewart (2002), looked at individual survival data from 3,004 patients from 12 randomized trials to compare survival after radiation plus chemotherapy versus irradiation alone. This analysis demonstrated a significant prolongation of survival from the use of chemotherapy with a hazard ration of 0.85 (p < 0.0001) and a 15 % relative decrease in the risk of death. This effect translated to an absolute increase in 1-year survival of 6 % with a 2-month increase in median survival time. This survival advantage was independent of differences in histology (anaplastic astrocytomas verses glioblastoma multiforme), age, sex, performance status or extent of resection. The combination of these early trials and meta-analyses identified chemotherapy with radiation therapy as a standard of care in patients with malignant gliomas in the US. A third analysis, evaluating patients in the temozolomide era confirmed these observations but had greater responses with longer duration of clinically significant benefit from temozolomide (Chamberlain and Chalmers 2007).

Concomitant Chemotherapy and Radiation

Radiation is an effective therapy for most MGs. Intensive research has led to improved understanding of cellular and molecular basis for radiation sensitivity and radioresistance. This work has led investigators to evaluate agents with the ability to enhance the therapeutic effect of radiation while minimizing additional toxicity. Although numerous compounds have been tested for a radiation sensitizing effect, chemotherapy drugs have been the most effective and form the basis of the evolving discipline of chemoradiation. Chemoradiation has been applied to MGs, initially with the nitrosureas (BCNU and CCNU). Other agents were also explored including cisplatin, fluorouracil, hydroxyurea, irinotecan, etoposide and paclitaxel. Several of the above regimens when dosed concurrently with radiation showed modest improvement in overall and progression-free survival in phase I and II trials, none however were effective enough to warrant a phase III trial (Colevas et al. 2003).

Temozolomide had pre-clinical data demonstrating benefit when given in conjunction to radiation therapy and was the impetus for a small phase II trial by Stupp et al. (2005) that showed a median overall survival of 16 months. This led to the larger trial from EORTC and NCIC that was published in 2005 (Stupp et al. 2005). Their phase III multi-center, randomized controlled trial randomly assigned 573 patients with histologically confirmed MG to receive radiotherapy alone or radiotherapy plus continuous daily temozolomide (75 mg/m2 × 42 days) while undergoing radiotherapy followed by six cycles of adjuvant temozolomide 150–200 mg/m² days 1–5 of a 28 day cycle. The median age of patients enrolled was 56 years, with 84 % of patients having undergone debulking surgery. The median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The 2-year survival rate was 26.5 % with radiotherapy plus temozolomide and 10.4 % with radiotherapy alone. The concomitant treatment with radiotherapy plus temozolomide resulted in higher toxicities in 7 % of the patients (Stupp et al. 2005). The above study has led this regimen to become the standard of care for patients with GBM and also to FDA approval for the treatment of newly diagnosed GBM. Although the results do not necessarily hold true for AG, many of these histologies are treated in a similar fashion. Follow up data suggests that the RT + TMZ group have maintained response out to 5 years (Stupp et al. 2005).

Multiple phase II trials have looked at the addition of compounds to the current standard of care utilizing temozolomide and concurrent radiation therapy, followed by adjuvant chemotherapy. Grossman et al. (2010) outlined three such compounds, talampanel, poly-ICLC, or cilengitide, given in addition to the standard temozolomide and radiation dosing for MG. This study found that the addition of a novel agent to radiation therapy and temozolomide resulted in a longer survival than similar patients treated only with the standard of care. The authors of this study are careful to warn that until the reasons for the varied survival rates are clarified, comparisons should be interpreted with caution, and that further phase III clinical trials are necessary to assess the benefit of additional compounds to temozolomide and radiation therapy (Grossman et al. 2010). One reason for improvement might be optimization of patient care from surgery, RT and chemotherapy and not that each agent added several months of benefit. This was borne out by RTOG 0525 where the median overall survival (OS) was approaching 16 months (Gilbert et al. 2011).

Chemotherapeutic Limitations

While chemotherapy in various forms has been effective in prolonging survival in MGs, by no means have they been curative, as resistance develops. Limitations of chemotherapy, when given either in the adjuvant or recurrent setting, are significant. Tumor penetration by chemotherapy can be limited due to tissue hypoxia, decreased perfusion into the mass due to a lack of blood supply and increased intra-tumoral pressure. With disruption of blood–brain barrier, specifically with MGs, many drugs can penetrate into the tumor but concentrations may not reach a therapeutic level especially in areas where the barrier remains intact. Another important limitation of chemotherapy is the interaction of chemotherapeutic agents with other medications used in brain tumor patients. Steroids are often utilized to control vasogenic edema, but in the process, they repair the blood–brain barrier thereby decreasing penetration and can interact with therapeutic agents. Older anticonvulsants often used either prophylactically or in the treatment associated with seizures related to MGs are hepatically metabolized and can have a significant drug-drug interaction with multiple chemotherapeutic agents which are typically utilized in the recurrent setting, like paclitaxel and irinotecan (Fetell et al. 1997).

Cellular mechanisms of resistance, intrinsic or acquired, may account for a lack of chemotherapeutic response. Mechanisms of resistance include overexpression of the repair enzyme O-6 alkylguanine-DNA-alkyltransferase (AGAT), also known as methylguanine methyl transferase (MGMT). High levels of MGMT correlate with increased resistance to cytotoxic effects of these agents and inversely correlate with response rates (Friedman et al. 1998; Jaeckle et al. 1998). Hegi et al. (2005) found that methylation status of MGMT gene promoter correlated with survival for patients treated with temozolomide. Methylation of the promoter led to an increase in median survival from 15.3 to 21.7 months for patients treated with radiation plus temozolomide compared with radiation alone. When the MGMT gene promoter is methylated, this acts as a silencing effect on the promoter, thereby not allowing for repair of the damage done by temozolomide and concurrent radiation (Esteller et al. 2000).

This MGMT silencing phenomenon has led to a phase III clinical trial (RTOG 0525) which stratified patients following initial concurrent treatment with temozolomide and radiation based upon methylation status to receive standard post-radiation temozolomide therapy (150–200 mg/m² days 1–5 of a 28 day cycle) versus dose-dense temozolomide (75–100 mg/m² days 1–21 of a 28 day cycle). This study showed no statistical significance between the two arms of therapy for median overall survival (16.6 monthsvs. 14.9 months, p = 0.63) or median progression free survival (5.5 months vs. 6.7 months, p = 0.06). The study did confirm the prognostic significance of MGMT methylation in GBM for newly diagnosed GBM regardless of methylation status (Gilbert et al. 2011).

Most of this data revolves around GBM. The optimal treatment for AG is more difficult in that some AGs are of oligodendroglial lineage and have better outcomes and no standard exists, only physician bias. For AAs, there is no standard recommendation for therapy after surgical resection. Historical data suggested PCV was better than BCNU but this turned out not to be the case (Prados et al. 1999). Data from the NOA 04 trial recently indicates that survival based on using radiation or chemotherapy with PCV or TMZ after surgery leads to similar outcomes when patients are then salvaged with the alternative treatment plan (Wick et al. 2009). Currently the CATNON trial is looking to define standard of care for patients with uni or non-deleted AGs.

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