Chemotherapeutics and Their Efficacy

Introduction

Glioblastoma (GBM), the most common primary brain malignancy, carries a poor prognosis and has therefore been the subject of numerous studies attempting to improve outcomes. Although a plethora of investigative studies and clinical trials have focused on this patient population, the median overall survival from time of diagnosis has remained largely unchanged over many decades, with a current range of 15 to 17 months and a median time to recurrence of approximately 7 months.

Traditional therapy was predicated on surgical resection or biopsy, if amenable; however, the highly infiltrative nature of these tumors renders complete resection nearly impossible. Accordingly, effective treatment relies on neoadjuvant and adjuvant therapy. Subsequent therapies have consisted of a combination of radiation with concurrent and adjuvant chemotherapeutics after surgical debulking with the current gold standard chemotherapeutic agent for newly diagnosed disease being temozolomide (TMZ), which is used concomitantly with radiotherapy.

Over the past decade, TMZ-based chemoradiotherapy has emerged worldwide as the standard therapy for newly diagnosed GBM. Although TMZ represents a landmark achievement in the treatment landscape of GBM because it remains the only chemotherapy agent that has definitively improved survival in a randomized controlled phase III trial in GBM, the absolute survival improvement is modest ( Table 9.1 ). Numerous novel therapeutic strategies for GBM are being developed. In this chapter, the historical context and rationale for chemotherapy in GBM are highlighted and the current gold standard reviewed. In addition, recent attempts to improve on the current standard are discussed with a focus on randomized controlled clinical trials given the plethora of early-stage clinical trials that have been conducted in GBM over the last several decades.

Context of current gold standard

In the past, the mainstay of GBM treatment solely consisted of surgical resection of the lesion. However, in 1978, Walker and colleagues showed a statistically significant increased overall survival in patients with anaplastic gliomas receiving either radiotherapy or 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU, or carmustine), a nitrosourea DNA-alkylating chemotherapy that penetrates the blood-brain barrier (BBB), compared with supportive care alone. This controlled, prospective trial randomized patients into 1 of 4 arms: BCNU, given as 80 mg/m ² /d on 3 consecutive days every 6 to 8 weeks; radiotherapy alone (5000–6000 rad to the whole brain); BCNU plus radiotherapy; and best supportive care. In the analysis of 222 patients who received any amount of therapy, there was a statistically significant improvement in overall survival with each of the 3 treatment arms compared with supportive care alone. However, the increases in median overall survival were small (18.5 weeks, 35 weeks, and 34.5 weeks for BCNU, radiotherapy, and BCNU plus radiotherapy, respectively, compared with 14 weeks for supportive care only), and the overall outcomes remained bleak. However, this study showed that both radiotherapy and BCNU had some efficacy in anaplastic gliomas, and, as a result, adjuvant radiotherapy in addition to surgical debulking of the lesion became standard therapy in these patients for decades to follow. Another finding of this study that would be a subject of further investigation was that the patients on the combined radiotherapy plus chemotherapy arm did not live significantly longer than patients treated with radiotherapy alone.

Later, chemotherapy agents used for other solid tumors were trialed in patients with GBM. In 1999, Friedman and colleagues published a single-arm study on the pharmacokinetics and preliminary efficacy of irinotecan, an alkaloid derivative of camptothecin and inhibitor of topoisomerase I originally marketed for colon cancer, in patients with recurrent or progressive malignant glioma. Preclinical studies of irinotecan showed promising results against a broad array of central nervous system neoplasms, prompting a phase II trial to further investigate its role in malignant glioma. The study enrolled 60 patients with recurrent malignant glioma treated with intravenous irinotecan at a starting dose of 125 mg/m ² given weekly for a 4-week cycle followed by a 2-week rest period. There were 15% confirmed partial responses and the 1-year median overall survival was 43 weeks, indicating moderate preliminary efficacy. By the early 2000s many other cytotoxic agents used for other cancers were studied in trials for malignant glioma, mostly using nitrosoureas such as carmustine or lomustine (CCNU) because these agents are lipid soluble and penetrate the BBB. However, most studies were inconclusive, and the median survival times for newly diagnosed GBM continued to be less than 1 year.

Eventually, a meta-analysis of patients from randomized trials comparing patients treated with radiotherapy alone versus radiotherapy plus nitrosourea-based chemotherapy was conducted, which suggested a small but statistically significant improvement in survival with the addition of chemotherapy to radiotherapy. Chemotherapy resulted in an apparent increase in median survival time of approximately 2 months compared with radiotherapy alone, with an increase in the 1-year survival rate of 6% (40% vs 46%). Although the effect of chemotherapy seemed modest at best, this analysis encouraged further study of chemotherapy in malignant glioma, with the focus on the imidazotetrazinone class of chemotherapeutic agents that crossed the BBB, such as dacarbazine and TMZ.

TMZ was developed in the 1980s at Aston University with support from the UK Cancer Research Campaign. Like earlier imidazotetrazinone derivatives, such as dacarbazine, TMZ converts to an active metabolite, 5-(3-methyl)1-triazen-1-yl-imidazole-4-carboxamide (MTIC). Advantageously, it spontaneously converted to the active agent after oral administration at physiologic pH without hepatic metabolism. MTIC is an unstable compound that quickly degrades into a methyldiazonium ion, which is a potent methylating agent. MTIC is readily available throughout the body, has excellent bioavailability, and, like nitrosourea compounds, has excellent penetration through the BBB. The drug acts as a major groove-directed DNA-alkylating agent methylating DNA at the N ⁷ and O ⁶ on guanine and the O ³ atom on adenine, with guanine O ⁶ and N ⁷ methylation being the main cytotoxic factors leading to apoptosis. In preclinical studies, TMZ showed antitumor activity in a wide variety of both intracranial and extracranial malignancies (reviewed by Friedman and colleagues ).

Yung and colleagues ultimately showed that TMZ had promising efficacy in a randomized phase II trial of patients with GBM at first relapse. This study showed that the 6-month progression-free survival rate (PFS6), which is the now-standard efficacy measure for recurrent GBM phase II trials, was improved with TMZ versus procarbazine (21% vs 8%). TMZ was given orally at 150 or 200 mg/m ² for 5 consecutive days on days 1 to 5 of each 28-day cycle. Although the study showed that TMZ had some activity against GBM, the median progression-free survival (PFS) rates remained modest (12 weeks) and the objective radiographic response rate was low (5.4%). In 1999, TMZ received US Food and Drug Administration (FDA) approval for second-line treatment of refractory anaplastic astrocytoma and GBM.

Later, combined radiotherapy and TMZ strategies were explored. Preclinical studies showed that concurrent TMZ and radiation resulted in at least additive cytotoxicity against several GBM cell lines in vitro. In 2002, Stupp and colleagues conducted a single-arm phase II trial of 64 newly diagnosed patients with GBM investigating concurrent daily fractionated radiotherapy with a continuous schedule of low-dose TMZ. The continuous TMZ schedule was originally designed as an attempt to mitigate a TMZ resistance mechanism mediated through the O ⁶ methylguanine-DNA methyltransferase (MGMT) enzyme, a DNA repair protein that rapidly reverses DNA alkylation at the O ⁶ position of guanine. Continuous TMZ exposure to TMZ resulted in depletion of MGMT in vitro, and this schedule was found to be safe in patients. Stupp and colleagues' study exploited this schedule, providing patients with concurrent 75 mg/m ² /d TMZ in addition to fractionated radiotherapy (total dose of 60 Gy given in 2-Gy fractions 5 times per week) for 6 weeks. Following this period, TMZ was given as monotherapy at a standard dose of 200 mg/m ² during days 1 to 5 of 28-day cycles for 6 cycles. The regimen was found to be safe and reported promising 1-year and 2-year survival rates of 58% and 31% with a median survival of 16 months.

The promising results of the phase II trial prompted a multi-institutional randomized phase III trial by the European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) Clinical Trials Group in patients newly diagnosed with GBM. Patients were randomized to receive either standard radiotherapy or concurrent radiotherapy with TMZ followed by 6 cycles of adjuvant TMZ in dosing described in the previous phase II study. A total of 573 patients were enrolled at 85 centers and overall survival was the primary end point. The median survival was 14.6 months with radiotherapy plus TMZ and 12.1 months with radiotherapy alone, and notably there was a significant improvement in the 2-year survival rate (26.5% for combined therapy vs 10.4% for radiotherapy alone). At 5-year follow-up, the survival results were sustained, with a significantly increased fraction of long-term survivors in the combination therapy group (5-year survival rate of 9.8% vs 1.9% in the radiotherapy-alone group). As a result of this study, the FDA approved TMZ for patients with newly diagnosed GBM in 2005 and this combined regimen of TMZ chemoradiotherapy became the standard of care.

In a companion molecular correlative study to the EORTC-NCIC phase III trial, Hegi and colleagues confirmed the positive prognostic impact of MGMT promoter DNA methylation. Methylation of the promoter silences expression of the MGMT gene, rendering cancer cells no longer able to produce MGMT protein, presumably limiting repair of DNA methylation induced by TMZ. Esteller and colleagues had earlier reported in a retrospective cohort of 47 patients with malignant glioma that MGMT promoter methylation was independently associated with response to nitrosourea therapy and increased overall survival. Using the same methylation-specific polymerase chain reaction assay, Hegi and colleagues found that, in the entire group of patients with GBM with evaluable MGMT status (206 patients), approximately half (44.7%) had MGMT promoter methylation, and this was also independently associated with significantly longer median overall survival (18.2 months for methylated vs 12.2 months for unmethylated MGMT promoter). Notably, Hegi and colleagues suggested that MGMT promoter methylation could predict response to TMZ. Within the subgroup of patients with methylated MGMT promoter, patients who received TMZ chemoradiotherapy lived significantly longer than patients who received radiotherapy alone (median overall survival, 21.7 months vs 15.3 months; P = .007). In patients without MGMT methylation, there was a small and marginally statistically significant improvement in overall survival for TMZ chemoradiotherapy compared with radiation alone (median overall survival, 12.7 months vs 11.8 months; P = .06).

TMZ has first-degree pharmacokinetics and excretion is predominantly renal, but dosing recommendations remain the same regardless of kidney function. Individual absorption is variable and the maximum plasma concentration occurs 30 to 90 minutes after ingestion, with an average volume of distribution of 171/m ² and cerebrospinal fluid concentrations 30% to 40% of plasma concentrations. The drug is more effective in the fasting state, with peak concentration delays occurring if taken with food; thus patients are encouraged to ingest on an empty stomach.

In addition to its global activity, TMZ also has an acceptable toxicity profile, especially compared with other agents in its class, such as mitozolomide, which was investigated and abandoned before TMZ. TMZ side effects include nausea and hematologic abnormalities, with thrombocytopenia and neutropenia being the most common and occurring in a dose-dependent fashion. In Stupp and colleagues’ 2002 phase II study, adverse events were mostly related to myelosuppression with lymphopenia, thrombocytopenia, neutropenia, and leukopenia occurring at rates of 55%, 4% to 19%, 8% to 14%, and 11% respectively. However, serious anemia, thrombocytopenia, and neutropenia, defined as Common Terminology Criteria for Adverse Events grade 3 or 4, was uncommon (5%–10%). Although rare, instances of Pneumocystis jiroveci ( Pneumocystis carinii ) pneumonia (PJP) and aplastic anemia have occurred, including PJP in 2 patients in the phase II trial, with the exact incidence unknown. Prophylactic PJP therapy given during the concomitant TMZ and radiotherapy treatment phase prevented further episodes in the phase II study. Mild side effects such as nausea and fatigue are also common with TMZ, with nausea being the most common with an estimated occurrence of 30%, which is generally successfully treated with antiemetics. However, serious nausea and fatigue are uncommon.