CHAPTER 112 Principles of Chemotherapy
The first line of treatment for primary brain tumors is surgery and radiation, yet these modalities alone are rarely curative for malignant tumors. Malignant tumors are infiltrative, and local therapy alone is not sufficient to eradicate all tumor cells. Cell cycle kinetic studies have shown that the cells that migrate into normal brain are the most viable and have the highest capacity for proliferation.1,2 The tumors therefore tend to recur after surgery or local radiation. Chemotherapy may be a means of treating these cells that escape local therapy.
It was only recently that chemotherapy became a standardized part of the treatment for newly diagnosed primary tumors. The landmark trial that established radiation and concurrent temozolomide (TMZ) followed by adjuvant TMZ as the current standard of care for newly diagnosed glioblastoma multiforme (GBM) was published by Stupp and colleagues in 2005.3 The median survival of patients receiving radiation and TMZ was significantly improved at 14.6 months compared with 12.1 months with radiation alone.
Before that major breakthrough, the role of chemotherapy was less well defined. A modest improvement in median survival with the addition of single-agent or combination chemotherapy had been demonstrated in several trials.4–6 Despite these positive results, it was difficult to ascertain the effectiveness of chemotherapy as adjuvant therapy, because improvements in survival were modest at best, reports had been conflicting, and many studies had been small. However, larger reviews and a meta-analysis demonstrated a survival benefit for those patients with malignant glioma treated with radiation and adjuvant chemotherapy compared with those treated with radiation therapy alone in the pre-TMZ era.6–9
Limitations of Chemotherapy
There are numerous obstacles or difficulties in attempting to treat central nervous system (CNS) tumors with chemotherapy. Malignant primary brain tumors represent a heterogeneous group of diseases. A variety of histologic subtypes may be seen within a single tumor (e.g., astrocytic cells adjacent to oligodendroglial components),10 and histologically similar tumors may not behave alike and often have different molecular and genetic profiles. This makes it difficult to target therapy to a single disease. In addition, the number of chemotherapeutic agents available to treat the variety of CNS tumors is limited. Since the 1960s, only four drugs (TMZ, carmustine [BCNU], lomustine [CCNU], and bevacizumab) have been approved by the U.S. Food and Drug Administration (FDA) for specific use in brain tumor patients.11
Drug resistance, either intrinsic or acquired, is common in tumors of the CNS, and many different mechanisms have been described. The best-characterized mechanism of drug resistance involves P-glycoprotein. P-glycoprotein is a drug efflux pump normally present on the luminal surface of brain capillary endothelial cells.12,13 It protects the neuronal environment of the CNS by excluding xenobiotics, including a variety of anticancer drugs, from the CNS.14–16 In addition to its presence on the endothelial cells of the blood-brain barrier (BBB), P-glycoprotein is overexpressed on the surface of some cancer cells, including brain tumors.17 The presence of P-glycoprotein on a tumor cell may restrict drug entry into the tumor cell or convey drug resistance.17 P-glycoprotein–mediated multidrug resistance is characterized by cross-resistance of tumor cells to several classes of chemotherapeutic agents.18
Poly (ADP-ribose) polymerase (PARP) is an abundant nuclear enzyme that mediates repair of DNA and also cell death. It also plays a role in the pathogenesis of cardiovascular and inflammatory diseases. PARP activation through mild to moderate genotoxic stimuli facilitates DNA repair by signaling cell cycle arrest and interacting with DNA repair enzymes such as XRCC1 and DNA-PK. Therapeutic DNA damage induced by certain chemotherapy agents (alkylating agents and topoisomerase I inhibitors) is largely dependent on PARP activation. As a result, DNA damage is repaired, tumor cells are rescued, and chemoresistance is induced. More severe DNA damage induces apoptotic cell death, whereby PARP is cleaved and inactivated by caspases.19
Other methods of drug resistance include the ability of tumor cells to repair DNA damage induced by cytotoxic agents or the use of alternative pathways of metabolism.20 O6-alkylguanine-DNA-alkyltransferase (AGT) is a DNA repair protein that removes alkyl groups from the O6 position of guanine. This is the site on DNA frequently targeted by alkylating agents, including CCNU, BCNU, and TMZ. In a number of human tumor cell lines and animal models, in vitro cytotoxicity of nitrosoureas was inversely related to AGT levels.21–23 Inactivation of AGT also improves response to temozolomide and nitrosoureas.24,25
Genetic Markers as Predictor of Chemotherapy Response
One example of genetic changes that have affected management of gliomas is the understanding of the role that chromosome 1p-19q codeletion plays in treatment-response and prognosis in patients with oligodendroglial tumors. The frequency of the combined 1p and 19q chromosome deletion in oligodendroglial tumors ranges from 40% to 70%, with higher rates in pure oligodendrogliomas.26 In anaplastic oligodendroglial tumors (AOTs), evidence is accumulating that those with 1p-19q codeletion have improved responsiveness to chemotherapy.27,28 Two phase III studies suggest that 1p-19q codeletion in AOT patients is an independent prognostic factor of better progression-free survival and overall survival whether they received chemotherapy as neoadjuvant or adjuvant treatment or in recurrence.29,30 Similarly, 1p-19q codeletion is a strong prognostic factor in low-grade gliomas31,32 and is associated with an improved response to chemotherapy, including procarbazine in combination with CCNU and vincristine (PCV) and TMZ.33,34
Another important marker of chemotherapy response in glial tumors is the epigenetic silencing of the AGT gene by promoter methylation. The AGT gene is located on chromosome 10q26 and encodes a DNA-repair protein that removes alkyl groups from the O6 position of guanine, an important site of DNA alkylation. As described previously, high levels of AGT create a resistant phenotype to alkylating agents. Conversely, epigenetic silencing of the AGT gene induces low expression of AGT and increased sensitivity to alkylating agents. In the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada (EORTC-NCIC) trial, AGT promoter methylation was present in 45% of cases. It was an independent favorable prognostic factor, and those patients benefited the most from the addition of TMZ.25
Principles of Central Nervous System Pharmacology
Systemic Drug Administration
Systemic drugs can be administered by a variety of routes. Some chemotherapeutic agents, such as TMZ, CCNU, and procarbazine, are given orally. Although oral administration is easier, oral therapy is complicated by varying degrees of bioavailability. Bioavailability depends on drug stability in gastric acid, absorption through gastric mucosa, inactivation by intestinal enzymes, hepatic metabolism and biliary excretion, and treatment-induced emesis.35 Administering the drug by an intravenous bolus gives a rapid maximal peak plasma concentration; the concentration then declines rapidly as the drug is distributed, metabolized, and excreted. This is best for agents that are not cell cycle specific (e.g., BCNU, cisplatin). Continuous infusion (intravenous administration for ≥24 hours) is used for agents that are cell cycle specific. In brain tumors, the actively dividing population is relatively small (5% to 10%), so continuous treatment maximizes the number of actively cycling cells that are exposed to sustained effective levels of drug.36
Blood-Brain Barrier
Systemically administered chemotherapeutic agents must cross the capillary endothelial cells of the cerebral vasculature to access tumor cells in the brain. These capillary endothelial cells differ from other endothelial cells in that they have extended tight junctions, lack fenestrations and pinocytotic vesicles, and express specific transport mediators.37 They form a relatively impermeable barrier between the blood and the brain, the BBB. The function of this single layer of specialized vascular endothelial cells is to maintain a precise neuronal environment, and it does so by limiting the entry of toxins into the brain parenchyma. The passage of substances across the BBB is limited by size, lipid solubility, and ionization state. Most hydrophilic substances and large (molecular weight > 180 daltons) lipophilic substances, which include many chemotherapeutic compounds, are restricted from entering the CNS.38 Smaller lipophilic compounds are able to pass through the BBB, penetrating the lipid membranes by simple passive diffusion. TMZ, nitrosoureas (BCNU, CCNU), and procarbazine are small lipophilic substances that can cross the BBB, and these have been the principal agents used to treat primary brain tumors.
Blood-Tumor Barrier
A similar barrier, the blood-tumor barrier, exists in brain tumor capillaries, limiting the delivery of cytotoxic agents to brain tumors.39,40 The vessels of some brain tumors have abnormally tight junctions and disrupted endothelial surfaces, which allow water-soluble contrast agents to cross the blood-tumor barrier; as a result, the tumor enhances on magnetic resonance imaging. The blood-tumor barrier tends to be more permeable than normal brain tissue, but the amount of drug reaching the tumor is still severely restricted. BBB breakdown in the area of the tumor is variable, and large areas exist where the BBB remains intact.39 In addition, the brain adjacent to tumor contains infiltrating tumor cells. These sites may be associated with an intact BBB, and drug delivery to this area is difficult.20 For moderately or even highly active drugs to ultimately affect the prognosis of patients with brain tumors, methods of delivering higher concentrations of chemotherapeutic agents to the tumor and proximal brain tissue must be developed.
Approaches to Overcome Obstacles of Chemotherapy
P-Glycoprotein Inhibition to Reverse Multidrug Resistance
A variety of drugs that inhibit P-glycoprotein have undergone preclinical and clinical testing as modulators of multidrug resistance.41,42 Examples of such agents are verapamil, cyclosporine, and cephalosporins. Because P-glycoprotein is normally expressed in several tissues, including the liver and proximal tubules of the kidney, it is thought to play a role in the elimination of toxins.43,44 In phase I studies, P-glycoprotein modulation decreased the clearance of anticancer drugs that are P-glycoprotein substrates and enhanced their toxicity, presumably because P-glycoprotein–dependent drug elimination pathways were inhibited.44 In addition, the maximal tolerated dose of the initial modulators was below levels that would cause significant P-glycoprotein inhibition.44 Despite these restrictions, objective responses have been demonstrated in phase II studies of lymphomas and myelomas.45,46 Newer, more potent, but less toxic P-glycoprotein modulators, such as cyclosporin PSC 833, are undergoing clinical trials. However, although P-glycoprotein is a theoretically attractive target for modulation to improve the delivery of chemotherapeutic agents to the CNS, the true contribution of multidrug resistance genes to brain tumor chemotherapy resistance remains speculative.
PARP Inhibition
Because of the involvement of PARP in the repair of DNA damage induced by certain anticancer agents or radiation,47,48 PARP inhibitors have been investigated as chemosensitizers and radiosensitizers for cancer treatment. GPI 15427 enhances the antitumor activity of TMZ against GBM, brain lymphoma, and intracranial malignant melanoma. When administered intravenously in combination with TMZ, GPI 15427 prolonged survival of tumor-bearing mice with reduction of the tumor mass and the number of sites of brain infiltration.49 Another preclinical study demonstrated that the PARP inhibitor CEP-6800 potentiates TMZ activity against subcutaneous GBM xenograft.50 A phase I study of the PARP inhibitor AG-014699 showed safety, significant inhibition of PARP, and antitumor activity in patients with advanced solid tumors.51 A phase I clinical study on the addition of the PARP inhibitor BSI-201 to radiation therapy and TMZ in patients with newly diagnosed malignant glioma is ongoing (see http://www.clinicaltrial.gov).
AGT Inhibition
Alkylating agents, such as CCNU, BCNU, and TMZ, have a predilection for methylating guanine at the O6 position.52,53 The resultant O6-methylguanine can be repaired by AGT, which confers resistance to these drugs, as described earlier. O6BG is a modulating agent that irreversibly inactivates and depletes AGT.54 In in vitro and in vivo tumor models, O6BG was able to potentiate the antitumor effects of TMZ.55,56 Early clinical trials have combined O6BG with TMZ and showed modest tumor response, depletion of AGT, and toxicity limited to myelosuppression.57,58 Clinical trials are ongoing to evaluate the efficacy of O6BG added to TMZ in recurrent and TMZ-resistant gliomas. Protracted exposure to TMZ leads to MGMT gene consumption and depletes the cell repair mechanism that may overcome the resistance of the tumor to the chemotherapy.59 Preclinical studies have demonstrated progressive depletion of MGMT following prolonged exposure to TMZ.60 Clinical trials are currently ongoing to assess whether a more intense schedule of TMZ will enhance its intrinsic cytotoxicity in malignant glioma.
Blood-Brain Barrier Disruption
Nonspecific osmotic disruption of the BBB has been clinically tested for the treatment of CNS malignancies. Neuwelt and coworkers demonstrated the feasibility of temporarily opening the BBB through intracarotid injection of osmotic agents to deliver higher doses of chemotherapeutic agents to the brain.61 The opening of the BBB is produced by shrinkage of endothelial cells and opening of the tight junctions. Cellular messenger systems such as calcium influx and nitrous oxide, as well as cytoskeletal changes, also contribute to this opening. Animal studies suggest that this method increases drug delivery to the brain 10- to 100-fold over injection into the neck arteries without the osmotic solution.62 Although a modest number of responses have been seen,63 the procedure can be associated with considerable toxicity; little additional chemotherapy is delivered to the bulk of the tumor, and more chemotherapy is delivered to normal brain areas, which may potentiate the neurotoxicity of chemotherapeutic agents.64–66
Biomodulation of specific receptors on the BBB may be a means of achieving therapeutic drug concentrations in the tumor and the brain around the tumor. Lobradimil (Cereport, RMP-7) is a bradykinin analogue that interacts with the B2 (bradykinin) receptor on the BBB, resulting in selective permeability of the BBB at the blood-tumor interface and a small area around the tumor.67,68 Phase I and II clinical trials administering lobradimil with the cytotoxic agent carboplatin, either intravenously or intra-arterially, have being conducted in an effort to deliver more of the chemotherapeutic agent to CNS tumors. Minimal efficacy was seen with this combination.69–73
High-Dose Chemotherapy
High-dose chemotherapy followed by autologous bone marrow transplantation or peripheral stem cell transplantation has been used in an attempt to improve the delivery of chemotherapy to CNS tumors. The rationale is increased delivery of chemotherapeutic agents across the BBB secondary to higher serum levels, resulting in greater tumor cell kill, given the steep linear-log dose-response relationship of alkylating agents74 and their cell cycle–independent cytotoxic properties.
High-dose chemotherapy has shown encouraging results, primarily for pediatric patients with relapsed medulloblastoma and intracranial germ cell tumors.74 It has also been used in young children to avoid the toxic effects of craniospinal radiation.74 The major problem with high-dose chemotherapy is the increased systemic toxicity. Although myelosuppression may be treated with the infusion of stem cells, other toxicities are then unveiled, including neurotoxicity associated with high-dose thiotepa, renal and ototoxicity associated with carboplatin, cardiovascular toxicity associated with cyclophosphamide, mucositis associated with etoposide, and pulmonary and hepatic toxicity associated with the nitrosoureas.74 The toxic mortality rate of high-dose chemotherapy for children with brain tumors ranges from 5% to 20%.74
High-dose chemotherapy with autologous stem cell rescue is significantly less promising in adults with malignant glioma. In general, response rates and overall survival have not been impressive, and toxicity has been substantial.75 This is not particularly surprising, given the fact that high-dose chemotherapy and autologous bone marrow transplantation have proved to be effective only in the most chemosensitive tumors. Unfortunately, most adult gliomas cannot be considered among this group.
Intra-arterial Therapy
Infusion of chemotherapeutic agents directly into the arterial supply of a tumor can provide a pharmacokinetic advantage by enhancing drug delivery to the tumor without increasing systemic drug exposure.76,77 This method may be more beneficial with drugs that undergo a large first-pass effect when given systemically and with drugs that have a high total-body clearance.78 Local plasma peak drug concentrations and local exposure are augmented compared with an equivalent intravenous dose, with less systemic toxicity.
A study by Levin and colleagues using radiolabeled BCNU demonstrated a fourfold increase in BCNU concentration in the brain after intracarotid administration compared with intravenous administration.79 In a study involving 12 adult patients with recurrent glioblastoma, intra-arterial BCNU infusion resulted in a median survival time of 54 weeks after recurrence (92 weeks after diagnosis), but no major improvement in survival was demonstrated in a group of 43 patients treated adjuvantly after receiving irradiation.80 It was hypothesized that the group receiving adjuvant intra-arterial BCNU had radiation-related changes that limited drug penetration into tissue,80 although the effects of radiation on drug delivery across the BBB have been controversial.
Nitrosoureas, cisplatin, and carboplatin have been given intra-arterially, with some responses noted.81–83 However, the responses have been modest, and the technique is associated with significant toxicity. In a study combining both intra-arterial and systemic chemotherapy in patients with grade II to grade IV gliomas, response rates up to 54% were demonstrated, but 31% of patients developed neurotoxicity, and 12% developed serious permanent local toxicity.84 No large, randomized trial has yet demonstrated that intracarotid administration of chemotherapy is more advantageous than systemic administration.85,86
One difficulty with intra-arterial administration is that there may be nonuniform drug distribution within the brain or the tumor after intracarotid infusion owing to poor mixing or streaming of the drug solution within the artery.87 Tissue regions that receive high concentrations of drug are at risk for toxicity, whereas low drug concentrations in other tissue regions may be subtherapeutic.88 In addition to increasing drug levels in the tumor, this technique increases drug levels in the area of normal brain supplied by the artery, leading to greater neurotoxicity. For example, intracarotid administration of BCNU has been associated with ocular toxicity, strokes, and an encephalitic picture.89
In adults, more brain tumors are supratentorial and are supplied by the carotid arteries, but more than 50% of childhood brain tumors are infratentorial.90 Infratentorial tumors are supplied by the vertebrobasilar arterial system, which is unique because of the convergence of the two vertebral arteries into the basilar artery. Cervical spinal cord toxicity has been described with carboplatin and etoposide injected in the vertebral artery in combination with osmotic BBB disruption.91
Interstitial or Intratumoral Drug Delivery
Given that most CNS tumors recur at, or very close to, the original tumor site,92 improving local control may translate into improved survival. Interstitial therapy involves administering drug directly into or adjacent to the brain tumor, circumventing the BBB. The theoretical advantages are increased local drug concentrations; decreased systemic exposure; and high, prolonged levels of the chemotherapeutic agent. Different strategies for intratumoral drug delivery include topical applications, Ommaya therapy, indwelling catheters, implantable drug delivery systems, and biodegradable polymers (wafers).
Biodegradable polymer matrices are molded wafers impregnated with a chemotherapeutic agent that is released in an active form for sustained periods in the area of the tumor. This technique increases a drug’s therapeutic efficacy by producing high local tissue concentrations over an extended period, with minimal systemic exposure.93 To effectively deliver drugs to the brain, several characteristics of the polymer are necessary: a biocompatible and biodegradable matrix, dependable and reproducible drug release, the ability to maintain the bioactivity of the therapeutic agent, and ease of surgical handling. Given the short plasma half-life of BCNU and its significant systemic toxicity, BCNU-impregnated biodegradable wafers have been studied.94 Wafers containing 3.8% BCNU allow sustained-release delivery and higher local concentrations for extended periods. Preclinical studies demonstrated that BCNU could be released from polymer disks for up to 21 days in rat and rabbit brain.95,96 Rats with implanted 9L gliomas that received BCNU-impregnated polymers demonstrated improved survival compared with controls with empty polymers.97
Gliadel wafers (MGI Pharma, Eisai, Woodcliff Lake, NJ) are now a surgical option for patients with newly diagnosed and recurrent single lesions compatible with malignant glioma without any communication with the ventricular system for which a nearly gross-total resection is possible.98 After pathologic confirmation of malignant glioma and maximal surgical tumor resection, up to eight wafers can be implanted in a patient depending on the size of the surgical cavity. Adjuvant treatment can be used in combination with the wafers (see later).
In a phase I trial of BCNU loaded in the PCPP-SA polymer in patients with recurrent glioma, the overall median survival was 46 weeks after implantation (87 weeks after initial diagnosis), with 86% of patients alive more than 1 year after diagnosis.99 No significant systemic toxicities were observed during this study. One major complication was the later development of neurological deterioration in a significant number (47%) of patients, which was thought to be due to development of necrosis around the wafer.
Gliadel has been further evaluated both as a therapy for newly diagnosed GBM100,101 and as a salvage therapy for recurrent GBM.102 A recent meta-analysis of the use of Gliadel for high-grade glioma concluded that the addition of Gliadel to radiotherapy led to increased survival relative to radiotherapy alone for newly diagnosed tumors but that there was no significant increase in survival with Gliadel therapy for recurrent disease.103 In a phase III trial randomizing patients with recurrent glioma to 3.85% BCNU polymer or empty polymer, there was a minimal but statistically significant improvement in median survival in the BCNU-treated group compared with the control group (31 weeks versus 23 weeks).102 Significant complications due to necrosis did not occur in this study.104 In the largest randomized controlled trial to date, patients who received Gliadel for newly diagnosed malignant glioma were reported to have experienced a 2-month improvement in median survival compared with patients who received placebo (P = .017).101 Experience has shown that Gliadel can be used safely in patients also receiving TMZ,105 and a phase II trial of Gliadel plus radiation and standard concurrent and adjuvant TMZ for newly diagnosed GBM is ongoing. Likewise, trials are under way to evaluate the use of Gliadel along with molecularly targeted agents for recurrent GBM.
Convection-Enhanced Delivery
In contrast to direct intracavitary delivery that relies on passive diffusion of drug, convection-enhanced delivery (CED) uses catheters to allow the delivery of various agents under continuous positive pressure, to evenly diffuse drug either directly into tumor or through the interstitial space of the brain around the resection cavity. The volume of distribution of the drug is influenced by a variety of factors: catheter placement, catheter shape, rate of infusion, volume of infusion, and physical properties of the injected agent (molecular weight, lipophilicity). Several agents tried in phase I and II trials have shown promising results, including transferrin-CRM107 and Cotara.106,107 A phase III trial with CED of cintredekin besudotox failed to demonstrate superiority over Gliadel wafers (P. Arndt, oral communication).
Pharmacology of Commonly Used Agents
Alkylating Agents
Temozolomide
TMZ is an oral prodrug derivative of the alkylating agent dacarbazine. It is rapidly absorbed and undergoes spontaneous hydrolysis at physiologic pH to form the active metabolite 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC).108,109 The mechanism of cytotoxicity is alkylation of DNA.110,111 Alkylation of the O6 position of guanine, N7 position of guanine, and N3 position of adenine are the lesions considered responsible for cytotoxicity. Oral bioavailability of TMZ is about 100%, and it has excellent penetration of the BBB and brain tumor tissue.
In the multi-institutional randomized, phase III EORTC-NCIC study, patients with newly diagnosed glioblastoma were randomized to receive radiotherapy plus continuous daily TMZ at 75 mg/m2 per day followed by six cycles of adjuvant TMZ at 150 to 200 mg/m2 on days 1 through 5 every 28 days. The median survival of patients receiving radiation and TMZ was significantly improved at 14.6 months, compared with 12.1 months with radiation alone.3 Quality of life was not negatively affected with the addition of TMZ, other than increased fatigue.112
TMZ is known to enhance the response of GBM to radiation in preclinical testing, and it is possible that the action of concurrent TMZ at the time of RT is responsible for most of the treatment effect.113 One single-institution case series of patients with newly diagnosed GBM described the use of radiation therapy with concurrent daily TMZ but without adjuvant therapy after radiation and reported results similar to the standard regimen.114 Nevertheless, most neuro-oncologists believe that adjuvant TMZ after radiation and concurrent TMZ does have additive value.
There has been concern recently that the use of TMZ in combination with radiation may be associated with increased postirradiation enhancement that stabilizes or decreases over time and that is thought to represent pseudoprogression rather than true disease progression. A formal retrospective analysis showed that the presence of pseudoprogression (as defined by no further enlargement of the enhancement on stable therapy for 3 months after radiation therapy) was associated with increased progression-free survival but not overall survival. Also, pseudoprogression was slightly more frequent with the combination of radiation and TMZ, compared with radiation alone, but not significantly.115 The rate of pseudoprogression immediately after radiation is between 24% and 50%, and it has been recommended that the immediate postirradiation scan be considered a new baseline and adjuvant TMZ continued, rather than changing therapeutic strategies.116,117
Different dosing regimens of TMZ have been reported in phase II studies. As discussed previously, there may be a benefit to protracted TMZ dosing because continuous dosing over 7 days may deplete MGMT.59 A review of a single-institution experience of three TMZ schedules was presented in abstract form.118 Overall survival of patients undergoing a standard schedule of 200 to 300 mg/m2 for 5 days every 28 days was compared with an extended schedule of 150 mg/m2 for 7 days every 15 days and to a daily continuous schedule of 75 mg/m2. Although this was not a prospectively designed randomized trial, myelotoxicity was less common, and overall survival appeared to be improved with the daily schedule of TMZ. A recent multicenter phase II study conducted by the Spanish Neuro-Oncology Group evaluated the activity of an extended TMZ regimen (85 mg/m2 per day) for 21 consecutive days every 28-day cycle in patients with TMZ-refractory malignant glioma and showed modest activity but manageable toxicity.119
In phase II testing of TMZ in patients with recurrent anaplastic astrocytoma, a combined response and stabilization rate of 60% was demonstrated, with a progression-free survival rate of 48% at 6 months.120 In another phase II study of patients with recurrent anaplastic astrocytoma or anaplastic oligoastrocytoma, 35% of patients demonstrated an objective response, and 26% had disease stabilization.121 Single-agent activity for recurrent glioblastoma appears to be significantly lower.
Because of its low toxicity profile, ability to cross the BBB, and good antitumor activity in adults, there has been much interest in using TMZ in pediatric brain tumors. Little benefit has been shown so far in phase II trials on malignant gliomas, but some interesting data were shown for medulloblastomas and primitive neuroectodermal tumors (PNETs) in phase I trials, and further studies as well as combination with other agents should be evaluated.122
TMZ is fairly well tolerated. Side effects include nausea, vomiting, constipation, diarrhea, thrombocytopenia, neutropenia, and anemia.121
Nitrosoureas
The nitrosoureas, which include CCNU and BCNU, are small, lipid-soluble, nonionized alkylating agents94,123 that spontaneously decompose into two active intermediates (an isocyanate group and a chloroethyldiazohydroxide).124 The chloroethyldiazohydroxide alkylates DNA, leading to formation of DNA-DNA cross-links and DNA-protein cross-links. The isocyanate group produces carbamoylation of amino groups, depleting glutathione, inhibiting DNA repair, and interfering with RNA synthesis. Because they are small and lipophilic, these agents readily cross the BBB. After systemic administration, CCNU concentration in the brain is equivalent to that in plasma, and BCNU concentration in the brain is 15% to 70% of that in plasma.78
Nitrosoureas were the primary single-agent therapy used for the treatment of gliomas in the pre-TMZ era.125 Several studies suggest that adjuvant therapy with nitrosoureas modestly improves survival for patients with malignant primary brain tumors,126–129 although a number of other trials have failed to demonstrate any survival advantage. Whether this discrepancy reflects the lack of statistical power to detect minimal antitumor activity in smaller clinical trials or a true lack of antitumor activity remains unclear. Prior randomized trials have also failed to control for variables known to be extremely important in the prognosis of patients with glioma (e.g., age, performance status, histology). Therefore, the various trial outcomes may be biased by nonuniform distribution of these variables among treatment groups. One meta-analysis suggests that nitrosourea-based adjuvant chemotherapy provides a modest benefit in patients with anaplastic glioma but only a minimal benefit in those with glioblastoma. This benefit is probably restricted to the small group of patients with the best prognostic factors (i.e., young, with minimal postoperative tumor and good performance status).7
The major toxicities associated with nitrosoureas are nausea, emesis, myelosuppression, pulmonary fibrosis (mainly with BCNU), and renal toxicity. The myelosuppression is cumulative (i.e., worsens with subsequent doses) and is typically delayed, occurring 3 to 5 weeks after treatment.130
Platinums
The platinum compounds cisplatin and carboplatin are cell cycle–nonspecific, bifunctional alkylating agents with demonstrated efficacy in adult and childhood primary brain tumors.131–133 The cytotoxicity depends on the free, or unbound, fraction of drug. The platinum compounds alkylate the N7 position of guanine, producing interstrand and intrastrand cross-links. Both agents are water soluble and poorly penetrate the BBB.134
Cisplatin has demonstrated variable activity against a wide range of tumors, including anaplastic astrocytoma, GBM, medulloblastoma, PNET, CNS lymphoma, and germ cell tumors.131,132,135,136 It can be given as a single agent or in combination with other drugs. In children, cisplatin as a single agent is efficacious for recurrent medulloblastoma, PNET, and ependymoma.137,138 Intra-arterial cisplatin has been used with modest result in recurrent gliomas.82 A recent retrospective analysis of 160 patients treated in the pre-TMZ era with a combination of cisplatin and carmustine showed progression-free and overall survival rates that were comparable to TMZ (7.6 and 15.6 months, respectively) but showed significant increased toxicity (hematologic and gastrointestinal), discouraging the use of this regimen.139
In combination with CCNU or cyclophosphamide plus vincristine (Packer’s regimen), cisplatin also has efficacy against high-risk and recurrent medulloblastomas.140 Cisplatin has considerable side effects, which include severe nausea and vomiting (acute or delayed), nephrotoxicity, ototoxicity, myelosuppression, and peripheral neuropathy. Side effects are common, and frequent dose reductions are necessary.
Carboplatin is a cisplatin analogue with a similar activity profile and comparable cytotoxicity in vitro. It is more myelosuppressive than cisplatin but causes less ototoxicity, nephrotoxicity, nausea, emesis, and peripheral neuropathy. It also has a higher unbound (active) fraction in plasma and greater CSF exposure than cisplatin.132,141 As a single agent, carboplatin has demonstrated efficacy in children for both low-grade glioma and recurrent malignant primary brain tumors.142,143 In adults, single-agent carboplatin showed minimal activity for the treatment of recurrent malignant glioma.144 Carboplatin has been used intra-arterially with significant optic and otic toxicity.145
Procarbazine
Procarbazine is an oral prodrug that is rapidly absorbed and metabolized to a lipid-soluble azoprocarbazine.146 This metabolite is then converted into two active derivatives by the cytochrome P-450 system. The active derivatives alkylate DNA at the O6 position of guanine. It can also induce DNA strand breakage and inhibit DNA, RNA, and protein synthesis. Although it is water soluble, procarbazine crosses the BBB, with rapid equilibration between plasma and CSF.78
Procarbazine can be used as a single agent or in multiagent regimens to treat malignant primary brain tumors. Procarbazine in combination with CCNU and vincristine (PCV) was compared with single-agent BCNU as postirradiation therapy in a randomized trial. There was no significant difference in overall survival or time to tumor progression for the group as a whole. However, in the subset of patients with anaplastic glioma (rather than glioblastoma), there was a significant difference in time to progression and survival for the group receiving PCV. It is important to realize that this survival advantage was demonstrated only in the subset analysis of a very small group of patients. A retrospective analysis of the Radiation Therapy Oncology Group database including more than 400 patients with anaplastic glioma revealed no survival advantage for patients treated with postirradiation PCV compared with BCNU.147 Procarbazine has also been reported by some investigators to be beneficial for patients with malignant glioma that recurs after radiation and nitrosourea therapy,148 but others suggest that it is significantly less active in patients previously exposed to nitrosoureas.149
Procarbazine is easy to administer and generally well tolerated. The primary side effects are myelosuppression, nausea and vomiting, fatigue, rash, and neurotoxicity.148 The dose-limiting toxicities are neutropenia and thrombocytopenia.78 Procarbazine also inhibits monoamine oxidase and has a disulfiram-like effect. Patients must be cautioned to avoid sympathomimetic drugs, antihistamines, tricyclic antidepressants, and foods high in tyramine content (wine, beer, cheese, chocolate, bananas, yogurt) because ingestion of these agents can cause acute hypertension or other interactions.123,150 Additionally, procarbazine can be associated with an acute hypersensitivity reaction resulting in life-threatening interstitial pneumonitis, particularly in patients previously shown to be allergic to the drug.151
Alkaloids
Vincristine
Vincristine is a plant alkaloid that acts as a cell cycle–specific agent. It enters cells through an energy-dependent carrier-mediated transport system and binds to tubulin during the S phase of the cell cycle, preventing polymerization and inducing metaphase arrest.124 Vincristine is water soluble and poorly penetrates the BBB.152 It undergoes extensive metabolism in the liver and is excreted primarily in the bile. Despite its limited CNS penetration, vincristine is said to have activity as part of multiagent regimens against low-grade glioma, medulloblastoma, oligodendroglioma, and anaplastic astrocytoma.153–155 It is important to note, however, that vincristine has never been rigorously evaluated as a single agent for primary brain tumors. Its primary side effects are neuropathy, constipation, and the syndrome of inappropriate antidiuretic hormone.124 The dose-limiting toxicity is usually peripheral neuropathy.
Topoisomerase Inhibitors
Irinotecan
Irinotecan (CPT-11, Camptosar) is a camptothecin derivative that is less toxic than the parent compound. Camptothecin is the active agent derived from the bark extract of the Camptotheca acuminata tree. Irinotecan is a prodrug that requires de-esterification by carboxylesterases to yield SN-38, a metabolite that is 1000 times more active at inhibiting topoisomerase I.156,157 Several oxidative metabolites of CPT-11 have been identified in humans, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin (NPC), generated by cytochrome P-450 3A4 (CYP3A4).158 Because of its hepatic metabolism, the dose of irinotecan has to be adjusted when patients are on enzyme-inducing antiepileptic drugs. The mechanism of action of irinotecan is stabilization of the covalent adduct between topoisomerase I and the 3′-phosphate group of the DNA backbone. The re-ligation reaction catalyzed by topoisomerase I is inhibited, ultimately leading to multiple DNA single-strand breaks. It also inhibits DNA and RNA synthesis, causing arrest of cells in the G2 phase of the cell cycle.158,159
Irinotecan has a broad range of activity against CNS xenografts.160 Single-agent irinotecan was tested in a phase II trial in recurrent malignant glioma and not found to have appreciable activity compared with historical controls.161,162 Response rates in GBM patients have been 14% to 15%, and stable disease has been achieved in 14% to 55%.162,163 Irinotecan, in combination with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF-A) has been shown in a phase II study to improve response rate (57%) and 6-month progression-free survival (46%) compared with historical controls,164 and in May 2009, bevacizumab received accelerated approval by the FDA for treatment of recurrent glioblastoma. A company-sponsored phase II trial of bevacizumab monotherapy compared with bevacizumab in combination with irinotecan showed a trend toward improved outcome with combination therapy, but the difference was not statistically significant.165 A phase III trial is needed to more fully define the risks and benefits of the addition of irinotecan to bevacizumab therapy. Further studies of bevacizumab, including combination therapy trials with other targeted agents, are ongoing.
Toxicity of irinotecan consists of myelosuppression, mild nausea and emesis, acute and delayed diarrhea, and hypotension.156,157
Etoposide
Etoposide (VP-16) is a highly lipophilic agent but does not readily cross the BBB.123 It causes single- and double-stranded breaks in DNA through interactions with DNA topoisomerase II and induces arrest in the G2 phase of the cell cycle. It also binds to tubulin and inhibits microtubule assembly.123 Etoposide has been demonstrated to have minimal activity as a single oral agent in some patients with malignant glioma,166,167 but for the most part, it is not considered a particularly useful drug for this indication. Etoposide does have activity in several pediatric brain tumors, including PNETs and primary CNS germ cell tumors, and it has been used successfully in combination with platinum compounds.
Etoposide has been used in a variety of schedules using different routes of administration, including oral, bolus intravenous infusion, or continuous intravenous infusion over several days. When given orally, a higher dose is required because of the decreased bioavailability.123 The major side effects are nausea, vomiting, neutropenia, and thrombocytopenia. A mild peripheral neuropathy may also occur.123
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