Oncology 2014;87:321–329 DOI: 10.1159/000362389 Received: March 18, 2014 Accepted: March 18, 2014 Published online: September 6, 2014
© 2014 S. Karger AG, Basel 0030–2414/14/0876–0321$39.50/0 www.karger.com/ocl
Review
Treatment of Brain Metastases Rimas V. Lukas a
Patrik Gabikian d
Madeline Garza b
Steven J. Chmura c
Departments of a Neurology, b Psychology, and c Radiation and Cellular Oncology, University of Chicago, Chicago, Ill., and d Department of Neurosurgery, Kaiser Foundation Hospital, Los Angeles, Calif., USA
Key Words Neoplasm metastasis · Brain · Brain metastases · Neurosurgery · Radiotherapy · Radiosurgery · Chemotherapy · Temozolomide · Bevacizumab · Ipilimumab Abstract Brain metastases are associated with substantial morbidity and mortality. Key prognostic classification systems for brain metastases are reviewed. The role of surgery, particularly for single brain metastases, is discussed. This is followed by an overview of radiation, both whole brain and focal, in the treatment of brain metastases. Finally, we review examples of important concepts regarding the role of systemic therapy in the treatment of brain metastases. © 2014 S. Karger AG, Basel
Introduction
Rimas V. Lukas Department of Neurology, University of Chicago 5841 South Maryland Avenue, MC 2030 Chicago, IL 60637 (USA) E-Mail rlukas @ neurology.bsd.uchicago.edu
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Approximately 1.6 million people were diagnosed with cancer in the USA in 2012 leading to more than half a million deaths [1]. Central nervous system (CNS) metastases are associated with significant morbidity and mortality and may represent the leading source for cancer of the CNS. The brain is the most common site of metastases in the CNS with brain metastases noted in approximately one quarter of all cancer patients at autopsy. However, in population-based studies, the incidence of clinically significant brain metastases is low [2]. Brain metastases are associated with over 130,000 mortalities each year in the USA with the majority of patients experiencing severe neurological impairments [3]. With improvements in imaging technology and screening, an increasing incidence of brain metastases will likely be observed [4]. With continued improvement of control of extra-CNS disease, brain metastases will become an increasingly important site of disease to address in the metastatic patient.
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Oncology 2014;87:321–329 © 2014 S. Karger AG, Basel www.karger.com/ocl
DOI: 10.1159/000362389 Lukas et al.: Treatment of Brain Metastases
Table 1. Variables influencing prognosis in brain metastasis patients in the RTOG-RPA and DS-GPA systems
RTOG-RPA
DS-GPA
all histologies
lung cancer
breast cancer
melanoma
renal cell cancer
gastrointestinal cancer
KPS Age Presence of ECM
KPS Age Presence of ECM Number of BM
KPS Age
KPS
KPS
KPS
Number of BM
Number of BM
Control of primary tumor Molecular subtype
Prognosis of Patients with Brain Metastases Accurate prognosis of patients with brain metastases helps guide management. Several different prognostic classification systems exist for patients with brain metastases. We will touch on the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) classification system and the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) to provide understanding of the system which will play an important role in future clinical trials as well as a historical perspective on the system used in the clinical trials which define our current management. The older of the two, the RTOG-RPA prognostication system stratifies patients into one of three classes using four factors: age, Karnofsky Performance Score (KPS), presence of extracranial metastases, and the control status of the primary tumor. Distinctions are not made between different histologies in this prognostication system. Patients 4 brain metastases is not yet clearly defined.
The role of systemic therapy for the treatment of brain metastases is less established than the role of surgery or RT. At this time, there is no role for upfront systemic therapy for newly diagnosed brain metastases outside of a clinical trial [35]. Salvage systemic therapy may be considered as an option in patients with a reasonable performance status. As with extra-CNS disease, systemic therapy options for brain metastases should consider the tumor histology and, when appropriate, its molecular characteristics. Additionally, systemic therapeutic options for brain metastases should either be able to cross into the CNS at effective concentrations or have an extra-CNS effect which can impact intra-CNS tumors. While we cannot cover every systemic therapeutic agent investigated for brain metastases, we will discuss specific examples which aim to treat brain metastases by either of these mechanisms. When considering the potential efficacy of systemically administered therapies for the treatment of brain metastases, we are hampered by inadequate knowledge of the concentrations of many agents in the brain and in brain metastases. This is a direct result of the difficulty of sampling both the brain and brain metastases in humans. For many agents, data is limited to animal models or in humans to proxies of brain/brain metastases concentrations such as cerebrospinal fluid concentrations. One of the better studied chemotherapies is temozolomide (TMZ), an alkylating agent approved for the treatment of high-grade gliomas. TMZ has been looked at in a number of lung cancer trials, particularly non-small cell lung cancer. Initial trials of single agent TMZ in recurrent/progressive brain metastases demonstrated tolerability as well as stability of disease with a small number of patients demonstrating complete responses [36, 37]. TMZ has since been looked at in combination with other chemotherapies such as capecitabine and vinorelbine for the treatment of brain metastases without clear evidence of benefit [38, 39]. Whether combination regimens using TMZ will provide additional benefit is yet to be determined. Two agents, an antiangiogenic therapy and an immunotherapy, will be discussed to illustrate how agents which do not cross the blood-brain barrier may have potential beneficial effects on the treatment of brain metastases. The first, bevacizumab, is a monoclonal antibody blocking vascular endothelial growth factor which is used in the treatment of recurrent highgrade gliomas as well as extra-CNS solid tumors. While there is evidence that large molecules such as antibodies are able to enter the CNS in patients with a more porous blood-brain/bloodtumor barrier, it is felt that the majority of bevacizumab’s activity on brain tumors occurs via its interactions with vascular endothelial growth factor on the luminal side of the endothelium. A number of clinical trials evaluating bevacizumab in combination with other chemotherapeutic agents in patients with solid tumor brain metastases have been completed [40–43]. While the majority of these studies included patients both with and without brain metastases, the PASSPORT open-label phase II trial (AVF3752g) specifically evaluated safety of bevacizumab in previously treated brain metastases [44]. Initial concerns regarding a markedly increased risk of intracranial hemorrhage (ICH) with the use of antiangiogenic therapies in
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Systemic Therapy
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Oncology 2014;87:321–329 DOI: 10.1159/000362389
© 2014 S. Karger AG, Basel www.karger.com/ocl
Lukas et al.: Treatment of Brain Metastases
patients with brain metastases, particularly those due to lung cancer, have diminished. No grade ≥2 CNS hemorrhages were reported in the PASSPORT trial [44]. Other studies have reported a low incidence of ICH in patients with brain metastases receiving bevacizumab. However, the mortality rate associated with these ICH is high. An association with ICH and other medications associated with an increased risk of bleeding was observed in brain metastasis patients treated with bevacizumab [45]. In turn, it is difficult to ascertain the contribution of bevacizumab towards the risk of ICH. The CNS is deemed to be a relatively immune privileged site. Recent advances in enhancing immune activity have proven to be beneficial in treating extra- and intra-CNS cancer. As an example we will focus our attention on ipilimumab, an antibody which blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4). Blocking of CTLA-4 decreases the inhibition of cytotoxic T cells, in turn augmenting their anticancer response. An open-label phase II trial investigating the safety and efficacy of ipilimumab in patients with melanoma brain metastases demonstrated stability of disease or partial/complete responses in some patients. These results were seen without any marked increase of morbidity due to ipilimumab [46]. A retrospective evaluation of patients with melanoma brain metastases treated with ipilimumab notes a median OS of 14 months [47]. The use of ipilimumab in conjunction with SRS for patients with a limited number of brain metastases does not appear to increase toxicity. No clearly apparent increase in control of CNS disease has been demonstrated either [48]. Conclusions
A multidisciplinary approach is often employed in the treatment of brain metastases. Appropriate prognostication helps guide the management as decisions are made regarding the various treatment modalities. At this time, RT is the central component of brain metastases treatment. Surgery plays an important role in specific clinical settings. The role of systemic therapy at this time is limited. Its importance, however, may grow. It is likely that, as our understanding of the processes broadly involved in CNS metastases are better understood, we will discover new means of treating and preventing CNS metastases. Common targets may exist which can be addressed across various histologies. In parallel, the importance of targeting the specific histological and, what will likely be more important, the molecular subtype of tumor in the CNS will also influence the evaluation of novel agents in clinical trials for brain metastases.
1 2 3 4 5 6
7
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Lukas et al.: Treatment of Brain Metastases
© 2014 S. Karger AG, Basel 0030–2414/14/0876–0321$39.50/0 www.karger.com/ocl
Review
Treatment of Brain Metastases Rimas V. Lukas a
Patrik Gabikian d
Madeline Garza b
Steven J. Chmura c
Departments of a Neurology, b Psychology, and c Radiation and Cellular Oncology, University of Chicago, Chicago, Ill., and d Department of Neurosurgery, Kaiser Foundation Hospital, Los Angeles, Calif., USA
Key Words Neoplasm metastasis · Brain · Brain metastases · Neurosurgery · Radiotherapy · Radiosurgery · Chemotherapy · Temozolomide · Bevacizumab · Ipilimumab Abstract Brain metastases are associated with substantial morbidity and mortality. Key prognostic classification systems for brain metastases are reviewed. The role of surgery, particularly for single brain metastases, is discussed. This is followed by an overview of radiation, both whole brain and focal, in the treatment of brain metastases. Finally, we review examples of important concepts regarding the role of systemic therapy in the treatment of brain metastases. © 2014 S. Karger AG, Basel
Introduction
Rimas V. Lukas Department of Neurology, University of Chicago 5841 South Maryland Avenue, MC 2030 Chicago, IL 60637 (USA) E-Mail rlukas @ neurology.bsd.uchicago.edu
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Approximately 1.6 million people were diagnosed with cancer in the USA in 2012 leading to more than half a million deaths [1]. Central nervous system (CNS) metastases are associated with significant morbidity and mortality and may represent the leading source for cancer of the CNS. The brain is the most common site of metastases in the CNS with brain metastases noted in approximately one quarter of all cancer patients at autopsy. However, in population-based studies, the incidence of clinically significant brain metastases is low [2]. Brain metastases are associated with over 130,000 mortalities each year in the USA with the majority of patients experiencing severe neurological impairments [3]. With improvements in imaging technology and screening, an increasing incidence of brain metastases will likely be observed [4]. With continued improvement of control of extra-CNS disease, brain metastases will become an increasingly important site of disease to address in the metastatic patient.
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Oncology 2014;87:321–329 © 2014 S. Karger AG, Basel www.karger.com/ocl
DOI: 10.1159/000362389 Lukas et al.: Treatment of Brain Metastases
Table 1. Variables influencing prognosis in brain metastasis patients in the RTOG-RPA and DS-GPA systems
RTOG-RPA
DS-GPA
all histologies
lung cancer
breast cancer
melanoma
renal cell cancer
gastrointestinal cancer
KPS Age Presence of ECM
KPS Age Presence of ECM Number of BM
KPS Age
KPS
KPS
KPS
Number of BM
Number of BM
Control of primary tumor Molecular subtype
Prognosis of Patients with Brain Metastases Accurate prognosis of patients with brain metastases helps guide management. Several different prognostic classification systems exist for patients with brain metastases. We will touch on the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) classification system and the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) to provide understanding of the system which will play an important role in future clinical trials as well as a historical perspective on the system used in the clinical trials which define our current management. The older of the two, the RTOG-RPA prognostication system stratifies patients into one of three classes using four factors: age, Karnofsky Performance Score (KPS), presence of extracranial metastases, and the control status of the primary tumor. Distinctions are not made between different histologies in this prognostication system. Patients 4 brain metastases is not yet clearly defined.
The role of systemic therapy for the treatment of brain metastases is less established than the role of surgery or RT. At this time, there is no role for upfront systemic therapy for newly diagnosed brain metastases outside of a clinical trial [35]. Salvage systemic therapy may be considered as an option in patients with a reasonable performance status. As with extra-CNS disease, systemic therapy options for brain metastases should consider the tumor histology and, when appropriate, its molecular characteristics. Additionally, systemic therapeutic options for brain metastases should either be able to cross into the CNS at effective concentrations or have an extra-CNS effect which can impact intra-CNS tumors. While we cannot cover every systemic therapeutic agent investigated for brain metastases, we will discuss specific examples which aim to treat brain metastases by either of these mechanisms. When considering the potential efficacy of systemically administered therapies for the treatment of brain metastases, we are hampered by inadequate knowledge of the concentrations of many agents in the brain and in brain metastases. This is a direct result of the difficulty of sampling both the brain and brain metastases in humans. For many agents, data is limited to animal models or in humans to proxies of brain/brain metastases concentrations such as cerebrospinal fluid concentrations. One of the better studied chemotherapies is temozolomide (TMZ), an alkylating agent approved for the treatment of high-grade gliomas. TMZ has been looked at in a number of lung cancer trials, particularly non-small cell lung cancer. Initial trials of single agent TMZ in recurrent/progressive brain metastases demonstrated tolerability as well as stability of disease with a small number of patients demonstrating complete responses [36, 37]. TMZ has since been looked at in combination with other chemotherapies such as capecitabine and vinorelbine for the treatment of brain metastases without clear evidence of benefit [38, 39]. Whether combination regimens using TMZ will provide additional benefit is yet to be determined. Two agents, an antiangiogenic therapy and an immunotherapy, will be discussed to illustrate how agents which do not cross the blood-brain barrier may have potential beneficial effects on the treatment of brain metastases. The first, bevacizumab, is a monoclonal antibody blocking vascular endothelial growth factor which is used in the treatment of recurrent highgrade gliomas as well as extra-CNS solid tumors. While there is evidence that large molecules such as antibodies are able to enter the CNS in patients with a more porous blood-brain/bloodtumor barrier, it is felt that the majority of bevacizumab’s activity on brain tumors occurs via its interactions with vascular endothelial growth factor on the luminal side of the endothelium. A number of clinical trials evaluating bevacizumab in combination with other chemotherapeutic agents in patients with solid tumor brain metastases have been completed [40–43]. While the majority of these studies included patients both with and without brain metastases, the PASSPORT open-label phase II trial (AVF3752g) specifically evaluated safety of bevacizumab in previously treated brain metastases [44]. Initial concerns regarding a markedly increased risk of intracranial hemorrhage (ICH) with the use of antiangiogenic therapies in
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/13/2015 3:41:00 PM
Systemic Therapy
327
Oncology 2014;87:321–329 DOI: 10.1159/000362389
© 2014 S. Karger AG, Basel www.karger.com/ocl
Lukas et al.: Treatment of Brain Metastases
patients with brain metastases, particularly those due to lung cancer, have diminished. No grade ≥2 CNS hemorrhages were reported in the PASSPORT trial [44]. Other studies have reported a low incidence of ICH in patients with brain metastases receiving bevacizumab. However, the mortality rate associated with these ICH is high. An association with ICH and other medications associated with an increased risk of bleeding was observed in brain metastasis patients treated with bevacizumab [45]. In turn, it is difficult to ascertain the contribution of bevacizumab towards the risk of ICH. The CNS is deemed to be a relatively immune privileged site. Recent advances in enhancing immune activity have proven to be beneficial in treating extra- and intra-CNS cancer. As an example we will focus our attention on ipilimumab, an antibody which blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4). Blocking of CTLA-4 decreases the inhibition of cytotoxic T cells, in turn augmenting their anticancer response. An open-label phase II trial investigating the safety and efficacy of ipilimumab in patients with melanoma brain metastases demonstrated stability of disease or partial/complete responses in some patients. These results were seen without any marked increase of morbidity due to ipilimumab [46]. A retrospective evaluation of patients with melanoma brain metastases treated with ipilimumab notes a median OS of 14 months [47]. The use of ipilimumab in conjunction with SRS for patients with a limited number of brain metastases does not appear to increase toxicity. No clearly apparent increase in control of CNS disease has been demonstrated either [48]. Conclusions
A multidisciplinary approach is often employed in the treatment of brain metastases. Appropriate prognostication helps guide the management as decisions are made regarding the various treatment modalities. At this time, RT is the central component of brain metastases treatment. Surgery plays an important role in specific clinical settings. The role of systemic therapy at this time is limited. Its importance, however, may grow. It is likely that, as our understanding of the processes broadly involved in CNS metastases are better understood, we will discover new means of treating and preventing CNS metastases. Common targets may exist which can be addressed across various histologies. In parallel, the importance of targeting the specific histological and, what will likely be more important, the molecular subtype of tumor in the CNS will also influence the evaluation of novel agents in clinical trials for brain metastases.
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