High-grade glioma continues to impart poor prognosis in spite of maximal treatment. Attempted gross total surgical resection followed by concurrent temozolomide and radiation therapy has become standard of care for glioblastoma. Ongoing clinical efforts have been directed at the further development of radiosensitizing agents that exploit tumor biology to maximize effects of concurrently administered radiation. The current article outlines the scientific rationale for the use of radiosensitizing agents and preliminary results from clinical trials using a variety of these approaches.
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Concurrent use of radiation with a range of sensitizing agents, including various chemotherapeutic drugs, can augment treatment efficacy through several well-defined biologic pathways.
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Mechanisms of radiosensitization include spatial cooperation, cytotoxic enhancement, biologic cooperation, temporal modulation, and protection of normal tissues.
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Temozolamide is the only chemotherapeutic agent that has been shown to provide a survival advantage when included with standard radiation therapy as an initial adjuvant approach for glioblastoma, an effect that has been associated with radiosensitization.
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Several agents, including angiogenesis inhibitors, are currently being studied for potential use in radiosensitization.
Introduction
In spite of recent success in the treatment of various forms of systemic cancer, glioblastoma multiforme (GBM) remains resistant to most current therapies. Various tumor characteristics have contributed to this resistance, including diffuse infiltration at the time of diagnosis, significant cellular heterogeneity (both intratumor and intertumor), and the role of tumor stem/progenitor cells in reestablishment of resistant disease following cytotoxic treatments. Current standard treatment of GBM consists of the regimen established by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada Clinical Trials Group (NCIC) in a landmark phase III trial published in 2005. Following maximal surgical resection, patients are treated with 60 Gy involved-field radiation therapy (IFRT), in which the involved field is defined as the radiographically evident tumor along with a margin of 2 to 3 cm. Treatment is administered in 30 fractions of 2 Gy each over 6 weeks with concurrent daily doses of the alkylating chemotherapeutic agent temozolomide (TMZ) at 75 mg/m 2 . This standardized chemoradiation therapy is followed by TMZ alone at 200 mg/m 2 for 5 days every 4 weeks for a total of 6 months.
The development of this combined adjuvant approach stemmed from several decades of clinical effort to improve outcomes for patients with GBM. Early studies in the 1970s had shown median survival for patients with malignant glioma, treated with surgical resection alone, to be less than 4 months. A growing experience with postoperative radiation therapy to the brain was initiated in the late 1960s and early 1970s. The survival benefit of whole brain radiation (WBR) to greater than 50 Gy was shown through a large trial performed at the Montreal Neurology Institute in 1966 and confirmed by studies from the Brain Tumor Study Group within the National Institutes of Health in the 1970s. Higher dosing strategies were explored by Salazar and colleagues in the 1970s, who concluded that doses of 70 to 80 Gy were well tolerated by patients but did not eradicate tumor and did not significantly improve survival compared with the 60-Gy dose. Based on histologic changes seen in autopsy specimens of the patients receiving 70 to 80 Gy, they cautioned that higher doses than this would likely involve significant risk for extensive tissue necrosis.
By the mid-1970s, there was increasing interest in application of IFRT to high-grade glioma, based on increasing understanding from clinical experience that most tumors are localized and that focal treatment allows minimization of the complications of radiation. It was also during this time that early reports of successful stereotactic radiosurgery suggested that precise localization of radiation was both technically possible and could be of clinical benefit. The rationale for IFRT was validated by Hochberg and Pruitt, who reviewed autopsy and imaging data for patients with GBM. They concluded that microscopic disease was limited to a 2-cm margin of the primary tumor in 29 out of 35 patients examined, and that 90% of recurrences also occurred in this margin. Further, multifocal disease occurred in only 4% of untreated patients, and was always identified on imaging. Ramsey and Brand in 1973 randomized 34 patients to WBR versus limited-field radiation, and showed that there was a survival benefit to higher dose (60 Gy) IFRT versus lower dose (40 Gy) WBR. These results have been validated in numerous subsequent studies and, in conjunction with technical improvements such as the introduction of multileaf collimators and associated planning algorithms for linear accelerators, have become the standard of care.
There has similarly been a long history of correlative adjuvant therapy in GBM through the addition of chemotherapeutic agents. Temozolomide, a second-generation DNA alkylating agent, has been the only chemotherapeutic agent to show a clear survival benefit in combination with radiotherapy (RT). The recent EORTC/NCIC study, which established the current standard of treatment, compared surgical resection plus RT versus surgical resection plus RT plus temozolomide. Median survival for patients aged 18 to 70 years was 12.1 months for surgery and RT alone to 14.6 months for surgery and RT combined with temozolomide. In a 5-year follow-up to this initial study, the benefit of the addition of temozolomide durable throughout the period of follow-up. A recent review of all patients with GBM in the United States in the SEER (Surveillance, Epidemiology and End Results) database comparing 2 years before the institution of the EORTC/NCIC regimen as standard care (2002–2004) with 2 years after (2005–2007) shows a gain in median survival from 11.5 to 12.5 months in the same age group, confirming that the additive effects of TMZ are mild in terms of clinical efficacy.
New therapeutic approaches are needed to provide a significant survival advantage for patients with GBM. The potential usefulness of radiosensitizing agents has been an intriguing possibility for these purposes and is the topic of this article.
Radiosensitization: a conceptual basis
Radiosensitizers are agents that are broadly defined as those that enhance the efficacy of radiation. In response to the increasing combination of radiation and chemotherapeutic agents available for the treatment of cancer in the late 1970s, Steel and Peckham described 4 exploitable mechanisms of radiosensitization derived from the interaction of various therapeutic modalities. Their system was recently updated by Bentzen and colleagues to provide further clinical relevance and take into account the effects of newer chemotherapeutic agents that are not directly cytotoxic. This more recent system of classification consists of 5 mechanisms of radiosensitization, which are summarized in this article.
Spatial Cooperation
The purpose of radiation therapy is locoregional control of disease, whereas chemotherapeutic agents target systemic disease that may or may not be clinically apparent. This approach allows for intensification of treatment via radiation in tissues with the greatest disease burden. Because this effect is spatial, it does not require concurrent administration of the 2 modes of therapy, and sequential treatment is generally preferred to minimize toxicity. This strategy has been effectively used in the context of various types of metastatic disease.
Cytotoxic Enhancement
The primary mechanism through which cytotoxicity is induced by ionizing radiation is the formation of free radicals within target tissues, which subsequently lead to DNA damage. Cytotoxic enhancement refers to the ability of a chemotherapeutic agent, given concurrently with radiation, to enhance DNA damage in the irradiated tissue by facilitating damage or by inhibiting repair. This approach may include inhibition of DNA replication, inhibition of mitosis, or induction of redox stress.
Biologic Cooperation
Although cytotoxic enhancement includes targeted effects of radiation and a chemotherapeutic agent on a common cell population, biologic cooperation refers to the presence of synergistic effects exerted by the chemotherapeutic agent through either different effector mechanisms and/or the activity of different cell populations. Commonly cited examples of agents showing biologic cooperation are antiangiogenic agents (eg, bevacizumab [BEV]) and bioreductive agents.
Temporal Modulation
Temporal modulation is the enhancement of the so-called 4 R effects of radiation dose fractionation through concurrent administration of a chemotherapeutic agent. The Rs consist of (1) preferential repair of DNA in normal tissues, reducing the toxicity of radiation if administered in a single fraction; (2) reoxygenation of previously hypoxic, and therefore radioresistant, central portions of tumor following the killing of the well-vascularized peripheral portions of tumor; (3) treatment by successive fractions of tumor repopulation following cytotoxic insult; and (4) redistribution of surviving tumor cells through the cell cycle to the more radiosensitive G2 and M phases. Agents targeting DNA repair mechanisms may be involved in both temporal modulation and cytotoxic enhancement.
Protection of Normal Tissue
This mechanism refers to minimization of acute or late radiation toxicity through the administration of a systemic agent. An example is a free radical scavenger with preferential cytoprotective effects in normal tissues.
Through the aforementioned mechanisms, a variety of agents have been proposed to have radiosensitizing properties in clinical use for malignant glioma (outlined in Table 1 ). The remainder of this article provides a brief overview of several of these agents, focusing on proposed mechanism of action as well as initial clinical experience with their use.
| Class | Agent | Mechanism |
|---|---|---|
| Inhibition of DNA replication | ||
| Alkylating agents | Temozolomide | Covalent transfer of alkyl group to guanine, increased apoptosis, and G2/M cell cycle arrest |
| Carmustine | Covalent transfer of alkyl group to guanine, increased apoptosis | |
| Topoisomerase I inhibitors | Camptothecin | Stabilization of topoisomerase I–DNA complex, inhibition of DNA religation |
| Topotecan | Stabilization of topoisomerase I–DNA complex, inhibition of DNA religation | |
| Irinotecan | Stabilization of topoisomerase I–DNA complex, inhibition of DNA religation | |
| Topoisomerase II inhibitors | Doxorubicin | Stabilization of topoisomerase II–DNA complex, inhibition of DNA religation |
| Inhibition of mitosis | ||
| Microtubule stabilizers | Paclitaxel | Disruption of microtubule organization during mitosis |
| Microtubule destabilizers | Vinca alkaloids | Disruption of microtubule organization during mitosis |
| Verubulin | Disruption of microtubule organization during mitosis | |
| Augmentation of redox stress | ||
| Nitroimidazoles | Metronidazole | Depletion of free radical scavengers |
| Misonidazole | Depletion of free radical scavengers | |
| Novel agents | Tirapazamine | Depletion of free radical scavengers |
| Motexafin gadolinium | Depletion of free radical scavengers | |
| Inhibition of angiogenesis | ||
| Thalidomide derivatives | Lenalidomide | Inhibition of migration of endothelial cells |
| Novel VEGF Inhibitors | Bevacizumab | Monoclonal antibody against VEGF-A |
| Aflibercept | VEGFR mimic, competes with VEGFR-1 and VEGFR-2 | |
| Receptor tyrosine kinase inhibitors | Cediranib | Inhibits PDGFR, c-kit, all subtypes of VEGFR |
| Vandetanib | Inhibits EGFR, RET kinases, VEGFR-1, VEGFR-2 | |
| Sorafenib | Inhibits BRAF, PDGFR-β, c-Kit, RAS, p38 α, VEGFR-1, VEGFR-2 | |
| Cabozantinib | Inhibits VEGFR-2 and MET | |
| Dasatinib | Inhibits BCR-Abl and Src family tyrosine kinases | |
| Adnectins | CT-322 | Inhibits VEGFR-2 |
| Integrin inhibitors | Cilengitide | Inhibits signaling initiated by contact of cell with extracellular matrix |
| Alternate signal pathway inhibition | ||
| Receptor tyrosine kinase inhibitors | Erlotinib | Inhibition of EGFR |
Radiosensitization: a conceptual basis
Radiosensitizers are agents that are broadly defined as those that enhance the efficacy of radiation. In response to the increasing combination of radiation and chemotherapeutic agents available for the treatment of cancer in the late 1970s, Steel and Peckham described 4 exploitable mechanisms of radiosensitization derived from the interaction of various therapeutic modalities. Their system was recently updated by Bentzen and colleagues to provide further clinical relevance and take into account the effects of newer chemotherapeutic agents that are not directly cytotoxic. This more recent system of classification consists of 5 mechanisms of radiosensitization, which are summarized in this article.
Spatial Cooperation
The purpose of radiation therapy is locoregional control of disease, whereas chemotherapeutic agents target systemic disease that may or may not be clinically apparent. This approach allows for intensification of treatment via radiation in tissues with the greatest disease burden. Because this effect is spatial, it does not require concurrent administration of the 2 modes of therapy, and sequential treatment is generally preferred to minimize toxicity. This strategy has been effectively used in the context of various types of metastatic disease.
Cytotoxic Enhancement
The primary mechanism through which cytotoxicity is induced by ionizing radiation is the formation of free radicals within target tissues, which subsequently lead to DNA damage. Cytotoxic enhancement refers to the ability of a chemotherapeutic agent, given concurrently with radiation, to enhance DNA damage in the irradiated tissue by facilitating damage or by inhibiting repair. This approach may include inhibition of DNA replication, inhibition of mitosis, or induction of redox stress.
Biologic Cooperation
Although cytotoxic enhancement includes targeted effects of radiation and a chemotherapeutic agent on a common cell population, biologic cooperation refers to the presence of synergistic effects exerted by the chemotherapeutic agent through either different effector mechanisms and/or the activity of different cell populations. Commonly cited examples of agents showing biologic cooperation are antiangiogenic agents (eg, bevacizumab [BEV]) and bioreductive agents.
Temporal Modulation
Temporal modulation is the enhancement of the so-called 4 R effects of radiation dose fractionation through concurrent administration of a chemotherapeutic agent. The Rs consist of (1) preferential repair of DNA in normal tissues, reducing the toxicity of radiation if administered in a single fraction; (2) reoxygenation of previously hypoxic, and therefore radioresistant, central portions of tumor following the killing of the well-vascularized peripheral portions of tumor; (3) treatment by successive fractions of tumor repopulation following cytotoxic insult; and (4) redistribution of surviving tumor cells through the cell cycle to the more radiosensitive G2 and M phases. Agents targeting DNA repair mechanisms may be involved in both temporal modulation and cytotoxic enhancement.
Protection of Normal Tissue
This mechanism refers to minimization of acute or late radiation toxicity through the administration of a systemic agent. An example is a free radical scavenger with preferential cytoprotective effects in normal tissues.
Through the aforementioned mechanisms, a variety of agents have been proposed to have radiosensitizing properties in clinical use for malignant glioma (outlined in Table 1 ). The remainder of this article provides a brief overview of several of these agents, focusing on proposed mechanism of action as well as initial clinical experience with their use.
Related posts:
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Immunotherapy for Glioma
Clinical Trials of Small Molecule Inhibitors in High-Grade Glioma
Nanotechnology Applications for Glioblastoma
Use of Language Mapping to Aid in Resection of Gliomas in Eloquent Brain Regions
Quality of Life and Outcomes in Glioblastoma Management
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