Evidence-based approaches to chemotherapy for gliomas

Temozolomide

Temozolomide (TMZ) is an oral agent converted by the liver to the active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The antineoplastic effect results from alkylating the middle guanine residue of DNA, leading to defective mismatch repair and cell death. TMZ is used commonly in many central nervous system (CNS) regimens due to its many favorable characteristics including good oral bioavailability, limited protein binding, and good CNS penetration with measurable levels being achieved in the cerebrospinal fluid (CSF) and in brain parenchyma following oral administration. Considering these properties, TMZ may be used with different schedules and timing for treating many gliomas, CNS lymphoma, or selected brain or leptomeningeal metastases.

• Treatment Schedules . TMZ is often administered concurrently and/or adjuvant to radiation therapy.

• Concurrent Temozolomide. The most frequent regimen consists of TMZ administered at 75 mg/m ² per day for 6 consecutive weeks along with conformal RT according to the Stupp regimen. ^, The aim of this treatment is to increase in a synergistic way the effect of combined radiation and chemotherapy with acceptable tolerability, possibly as a result of a radiosensitizing effect of TMZ during radiation. Several trials have demonstrated a significant benefit of TMZ in newly diagnosed glioblastoma (GBM). Thus, chemoradiation represents the standard of care (SOC) for GBM in clinical practice and the main control arm in clinical trials with experimental drugs.

• Adjuvant Temozolomide. TMZ may also be administered adjuvantly or in the recurrent setting. Several different schedules may be employed. The most frequent schedule following chemoradiation consists of 150–200 mg/m ² per day for day 1–5 every 28 days for six cycles. Cycle 1 is administered at 150 mg/m ² per day and, if there is no unacceptable toxicity, this is escalated to 200 mg/m ² per day for the remaining cycles. The O-6-methylguanine-DNA methyltransferase (MGMT) gene plays an important role in the clinical response to TMZ. The MGMT enzyme is involved in repairing DNA following alkylating-induced damage such as those caused by TMZ. As a result, silencing of this gene (e.g., through methylation of the MGMT promoter) limits the cancer cells ability to survive TMZ-induced DNA damage and is associated with improved responses. Methylation of the MGMT promoter is associated with a better overall survival (OS) in newly diagnosed GBM. Clinical trials have also studied the use of “intensified” protocols to increase the total dose of TMZ delivered, deplete the amount of MGMT in the cell, and overcome treatment resistance. ^, These dose-dense regimens include schedules such as 75–100 mg/m ² per day for 3 weeks-on and 1 week-off, or 120–150 mg/m ² per day for 1 week-on and 1 week-off, or “continuous” administration at 50 mg/m ² per day for 28-out-of-28 days (e.g., metronomic). These schedules did not show improvement in OS as compared with standard schedules with a major risk of toxicity (see Case 4.4 : Newly diagnosed glioblastoma, later).

• Other Temozolomide Regimens. Other regimens have also been studied. TMZ has been investigated in the neoadjuvant setting (before conformal RT) in both grade III astrocytomas and GBM. There was no advantage in OS in GBM. Neoadjuvant TMZ in grade III astrocytoma resulted in a longer survival at 5 years. Preoperative TMZ in LGGs has also been suggested in order to decrease the tumor volume, amount of tumor infiltration, and facilitate a safer, more radical resection.

• Toxicity. In general, TMZ is well tolerated by most patients. The most frequent side effects are nausea/vomiting and fatigue. However, approximately 20% of patients discontinue TMZ due to myelosuppression, in particular for thrombocytopenia (<100,000/mm ³ ). Severe thrombocytopenia as defined by the common terminology criteria for adverse events (CTCAE) as grades 3 or 4 and prolonged thrombocytopenia occurs in about 5% of patients. Moreover, a rare idiosyncratic reaction may appear during chemoradiation with a severe decrease of red blood cells (<2 × 10 ⁶ /mm ³ ), hemoglobin (<8.0 g/dL), thrombocytes (<75,000/mm ³ ), and febrile neutropenia (<1,000/mm ³ ).

PCV chemotherapy: procarbazine, CCNU, and vincristine

Procarbazine (PC), lomustine (CCNU), and vincristine is a combined therapy administered in a 6-week cycle with CCNU on day 1, vincristine on days 8 and 29, and PC on days 8–21.

• PC is an oral alkylating drug with modest efficacy in HGGs when used as monotherapy. Fatigue, anorexia, and myelosuppression are the most frequent adverse events. Patients must follow a tyramine-free diet to avoid an excess tyramine catecholamine reaction.

• CCNU is an oral nitrosourea that is also the standard second-line chemotherapy in progressive HGGs in Europe. Toxicity includes cumulative myelosuppression, nausea/vomiting, fatigue, and, in rare cases, pulmonary fibrosis.

• Vincristine is a vinca alkaloid that interferes with microtubule formation and disrupts the tumor cytoskeleton. Typical side effects are a dose-dependent sensorimotor peripheral neuropathy, myelosuppression and constipation. Vincristine is commonly used in pediatric brain cancers because of the high sensitivity of glioma cells, whereas in adults it has a minor impact due to a poor penetration through the blood-brain barrier (BBB).

Typically, PC + CCNU + vincristine (PCV) chemotherapy is administered as an adjuvant treatment following RT in high-risk grade II and anaplastic gliomas (see Case 4.1 : Anaplastic gliomas with 1p19q co-deletion and Case 4.3 : Low-grade gliomas, later) or as a second-line chemotherapy in cases of recurrent of HGGs (see Case 4.6 : Treatment for recurrent high-grade gliomas, later) .

Nitrosourea chemotherapy

In addition to lomustine, fotemustine (diethyl 1-{1-[3-(2-chloroethyl)-3-nitro-soureido]ethyl} phosphonate (FTM) and carmustine (1,2-bis(2-chloroethyl)-1-nitrosourea; BCNU) are intravenous nitrosoureas used for treating CNS gliomas. These agents have favorable CNS characteristics, including high lipophilicity and low molecular weight, which makes, it easier to cross the BBB. The antitumor effect is based on alkylation of DNA and generation of cytotoxic damage. Similar to TMZ, the presence of methylation of MGMT confers a major sensitivity to FTM and BCNU. After intravenous infusion, the steady state is achieved within 45 minutes with a median half-life of 3 hours and a CSF concentration about 23% of plasma levels. The most important side effects are thrombocytopenia, leucopenia, and anemia. In contrast to cytopenias with temozolomide, which often remain reversible with blood counts returning to their pre-cycle baseline with each round of treatment, cytopenias with the nitrosourea compounds can be cumulative where blood counts fail to recover to their pre-cycle baseline prior to the next treatment.

Currently, CCNU, BCNU, and FTM are employed as a second-line chemotherapy in recurrent HGGs with CCNU/BCNU used in the United States and FTM used in some European countries (including Italy). They are also used as a single agent or in combination with targeted therapy (e.g., bevacizumab) in an off-label setting (see Case 4.6 : Treatment for recurrent high-grade gliomas, later).