Temozolomide has been available to oncologists for over 30 years. During this time, it has become an integral part of standard therapy in patients with high-grade gliomas. Given its ability to traverse the blood-brain barrier, temozolomide has also been evaluated in other cancers that involve the central nervous system (CNS). We review its role in the management of patients with primary brain tumors, brain metastases, leptomeningeal carcinomatosis, and other selected CNS cancers. There is strong evidence that temozolomide is effective in patients with high-grade astrocytomas and oligodendrogliomas. Modest evidence supports its activity in primary CNS lymphomas and aggressive pituitary adenomas. Temozolomide, however, has minimal efficacy in a wide variety of systemic cancers. Given that concentrations of temozolomide in the CNS are only 20% of those in the blood, it is not surprising that it is generally inactive in patients with CNS metastases from solid tumors.
Temozolomide was synthesized in the 1980s as a water-soluble imidazotetrazinone that exhibited excellent antineoplastic properties in vitro and in vivo.[1,2] At a pH greater than 7, it spontaneously hydrolyzes to its active form, which is the same active metabolite as in dacarbazine. Its novelty came from the fact that it is an orally bioavailable alkylating agent able to penetrate the blood-brain barrier due to its lipophilic nature.
Temozolomide functions by modifying DNA or RNA through the addition of methyl groups (alkylation) to guanine at the N7 and O6 sites, and to adenine at the O3 site. This causes substitution of thymine for cytosine during DNA replication, which creates a mismatched base pair. This in turn triggers the DNA mismatch repair pathway, which attempts to repair the damage but results in inappropriate DNA crosslinks, G2 arrest, and ultimately, leads to apoptosis (Figure).[4,5] The methyl group temozolomide adds can be repaired by some intracellular DNA repair programs, such as DNA mismatch repair or base excision, or it can be removed by O6-methylguanine-DNA methyltransferase (MGMT), a demethylating enzyme. The amount of methylation temozolomide causes within a cell is important for ensuring catastrophic cell death. Notably, the effect of temozolomide on DNA is independent of whether the cell is irradiated, but temozolomide synergizes with radiation to increase glioma cell death.
Temozolomide received accelerated approval from the US Food and Drug Administration (FDA) in 1999 for treatment-refractory anaplastic astrocytomas. It was later approved by the FDA for newly diagnosed glioblastoma administered concurrently with radiation therapy and for 6 months thereafter based on a phase III study. Since then, it has been a backbone of treatment for both newly diagnosed and recurrent high-grade astrocytomas and oligodendrogliomas.
Although the toxicities of temozolomide are modest compared with other chemotherapy agents, it can have significant side effects. When combined with brain irradiation, 20% of patients develop significant myelosuppression and some develop severe (grade 3/4) lymphopenia, which is long-lasting and associated with reduced survival and poor response to immunologic interventions. Use of temozolomide can also result in constipation, fatigue, and malaise and a small risk of secondary malignancies.
Blood-Brain Barrier Penetration of Temozolomide
Currently, 98% of drugs on the market do not penetrate the blood-brain barrier. Temozolomide’s small size (194 Da) and lipophilicity enhance CNS penetration relative to other alkylating agents. Despite this, the concentration of temozolomide in brain tumor tissue is about 20% of plasma levels. Concentrations in cerebrospinal fluid are similar, although levels may rise to 35% of plasma levels when given concurrently with radiation. Whereas this agent is effective for some tumors, its relatively low concentration in the CNS requires that the cancers being treated are very sensitive to temozolomide.
Many unsuccessful efforts have been made to improve the blood-brain barrier penetration of temozolomide and other systemically administered chemotherapeutic agents. Changing the dosing frequency (dose-dense regimens) or delivery method (through intra-arterial delivery) has resulted in higher toxicity rates without an improvement in patient outcomes.[13-16] Current studies are under way exploring the use of focused ultrasound, regadenoson, and nanoparticles to disrupt the blood-brain barrier or improve drug penetration.[17-19]
Effect of MGMT Status on Temozolomide Sensitivity
The efficacy of temozolomide may be influenced by gene expression within tumor cells. The most important of these is MGMT, a gene that encodes the protein O6-alkylguanine DNA alkyltransferase (AGT) and is responsible for removing methyl groups from DNA at the O6 position. Each AGT molecule is able to irreversibly remove one methyl group, after which it releases the DNA strand and is ubiquitinated and degraded. MGMT activity is regulated in part by promoter methylation, which turns off gene expression. Hypermethylation is frequently observed in some cancers causing MGMT silencing, and demethylation is associated with gene activity.
In glioma clinical trials, epigenetic silencing of MGMT through promoter methylation has been associated with increased DNA double-strand breaks and sensitivity to the alkylating agents BCNU [bis-chloroethylnitrosourea; carmustine] and temozolomide.[8,22,23] In fact, MGMT promoter methylation appears predictive of tumor sensitivity to temozolomide and is also an independent prognostic biomarker, because MGMT methylation is associated with improved survival independently of temozolomide.
Although MGMT methylation in gliomas is a predictive biomarker for temozolomide sensitivity and a prognostic biomarker, this does not appear to be the case in other cancers, such as colorectal cancer and non–small-cell lung cancer.[25-28] The one exception may be diffuse large B-cell lymphoma, in which MGMT methylation may correlate with improved overall survival, although it is not routinely tested in clinical practice and has no effect on treatment selection.[29,30]
Primary Brain Tumors
Glioblastoma (grade 4 astrocytoma) is the most common primary brain tumor in adults, affecting over 11,000 people each year in the United States. This cancer is most often diagnosed in older adults and is associated with a median survival of just over 1 year. Although these tumors may appear localized on magnetic resonance imaging, they are virtually never cured with aggressive surgery because tumor cells extend well beyond surgical margins. Radiation therapy is the most beneficial postoperative therapy for this disease, but unfortunately it does not have curative potential. Initial efforts to combine chemotherapy with radiation determined that the nitrosoureas, which cross the blood-brain barrier, were most effective. In prospective, randomized studies, however, the addition of these agents did not result in a substantial survival advantage.[32,33] In 2005, the results of an EORTC/NCIC trial that randomized patients with newly diagnosed glioblastoma to receive either radiation alone or radiation with concurrent and adjuvant temozolomide were published. This unconventional adjuvant trial design included patients with extensive residual tumor in a disease for which temozolomide had insufficient efficacy at recurrence for FDA approval.
Despite flouting conventional adjuvant clinical trial design, this trial convincingly demonstrated a survival advantage from the addition of temozolomide in newly diagnosed glioblastoma. Although the median survival of patients eligible for this trial improved from 12 to 14.6 months with the addition of temozolomide, survival improved from 10% to 26% at 2 years and from 0% to 10% at 5 years.. Additional analysis demonstrated that patients who are MGMT unmethylated derive much less benefit from the addition of temozolomide than those who are MGMT methylated. More recently, the findings of this study were replicated in patients older than age 65 years with newly diagnosed glioblastoma who were treated with a shorter course of radiation. As of 2018, temozolomide remains the only systemically administered pharmaceutical agent documented to provide a survival advantage to patients with glioblastoma.
The annual incidence of anaplastic astrocytomas (grade 3 astrocytoma) is about 1,300 cases/year in the United States, which is 10 times less frequent than that of glioblastoma. As a result, no large prospective, randomized studies exist documenting the magnitude of benefit from adding temozolomide to radiation in this population. The efficacy of temozolomide in patients with recurrent anaplastic astrocytomas, however, was found to be higher than its efficacy in patients with glioblastoma, leading to an approved indication by the FDA. As a result, many patients with newly diagnosed anaplastic astrocytomas, particularly those who are wild type for the isocitrate dehydrogenase (IDH) gene, receive radiation with concurrent and adjuvant temozolomide, just like patients with glioblastoma.
The treatment of patients with grade 2 astrocytomas is more controversial. These tumors may manifest with seizures in patients who are otherwise doing well. In this setting, low-risk patients are often followed closely after surgery without further treatment until there is clear evidence of tumor progression, which may be years later. High-risk patients typically receive treatment with radiation immediately after diagnosis. Risk factors for a poor outcome include age 40 years or older, preoperative tumor size of 5 cm or more, subtotal resection, lack of IDH mutation, lack of 1p/19q codeletion, and elevated mitotic index. The role of chemotherapy in these patients remains controversial. Studies have documented that the PCV regimen, which consists of procarbazine, CCNU [1-(2-Chloroethyl)-3-Cyclohexyl-1-Nitrosourea; lomustine], and vincristine, improves survival following radiation in low-grade gliomas, but the primary benefit appears to be in patients with low-grade oligodendrogliomas. This is not entirely unexpected, given that the PCV regimen has no significant benefit in patients with high-grade astrocytomas. As a result, it might be expected that temozolomide would be a more effective approach to low-grade astrocytomas, although no prospective, randomized study has compared PCV against temozolomide in grade 2 astrocytomas.[38-41] A single-arm study in high-risk, low-grade glioma shows benefit from the combination of temozolomide and radiation. As is the case in glioblastoma, MGMT promoter methylation status may be a marker for response to temozolomide in low-grade glioma, but convincing data are currently lacking.
Approximately 1,000 patients per year in the United States are diagnosed with oligodendrogliomas, which are defined by the presence of a 1p/19q codeletion based on current criteria from the World Health Organization. Of these, 70% have low-grade (grade 2) oligodendrogliomas, while 30% have anaplastic oligodendrogliomas (grade 3). Randomized, prospective trials have clearly demonstrated that radiation followed by PCV chemotherapy in patients with grade 2 and 3 oligodendrogliomas leads to a 7-year improvement in survival over radiation alone.[36,44,45] Efficacy of temozolomide monotherapy has also been demonstrated in newly diagnosed and recurrent oligodendrogliomas.[37-40] Currently ongoing is a randomized, prospective trial designed to determine whether radiation followed by PCV or radiation with concurrent and adjuvant temozolomide is the best regimen for patients with recently diagnosed oligodendrogliomas (NCT00887146). This study had a temozolomide-only arm that closed early because it was not as effective as the arms that contained radiation.
Ependymomas are rare tumors of the cells lining the ventricular cavity. These tumors can occur anywhere along the neuroaxis, but are typically found intracranially in children or within the spinal canal in adults. Treatment usually consists of maximal safe surgical resection, followed by radiation therapy in many cases. Chemotherapy may be used to avoid early irradiation in very young children, but otherwise it has a very limited role in the treatment of ependymomas. There are several case reports of individual responses to temozolomide in the setting of recurrent disease; however, larger retrospective reviews have shown very limited responses.[46-48] Although limited in scope, these data are generally in line with what is known about the resistance of ependymomas to chemotherapy and do not support general use of temozolomide in ependymomas.
Primary CNS lymphoma
Primary CNS lymphoma (PCNSL) is a rare malignancy that comprises 2% of all brain tumors and 2% of all lymphomas. It diffusely involves the brain, and 20% of the time, it is also present in the eyes or spinal fluid. It generally affects older patients. Due to its rarity, randomized clinical trials have been difficult to undertake and complete in this population. Initial treatment attempts focused on whole brain irradiation. The median survival following radiation was only 1 year, however, and the neurologic complications were significant in patients who lived long enough to experience them. As a result, efforts shifted to studying chemotherapy. Typical chemotherapy regimens for lymphomas were not effective, likely secondary to poor blood-brain barrier penetration. Unlike systemic lymphomas, PCNSL is very sensitive to high-dose methotrexate (HD-MTX) with an overall response rate of 74%. Resultantly, HD-MTX has become the base for all standard regimens in newly diagnosed patients. A standard regimen often includes rituximab, with the possible addition of cytarabine, temozolomide, or procarbazine/vincristine. It is unclear whether one of these combinations is superior, and the combination of multiple chemotherapeutic agents can increase toxicity, so a patient’s functional status is an important consideration when selecting a therapeutic regimen. The regimen with temozolomide, in particular, involves HD-MTX plus temozolomide and rituximab followed by consolidation with etoposide and cytarabine. It has shown a complete response rate of 66%, but with grade 3/4 toxicities in more than 55% of participants.
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