Accepted Manuscript Who Benefits from Surgery for Brain Metastases (Perspective)? Mohammed Abd-El-Barr, MD E. Antonio Chiocca, MD PhD PII:
S1878-8750(14)00268-X
DOI:
10.1016/j.wneu.2014.03.020
Reference:
WNEU 2308
To appear in:
World Neurosurgery
Received Date: 15 February 2014 Accepted Date: 11 March 2014
Please cite this article as: Abd-El-Barr M, Antonio Chiocca E, Who Benefits from Surgery for Brain Metastases (Perspective)?, World Neurosurgery (2014), doi: 10.1016/j.wneu.2014.03.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Who Benefits from Surgery for Brain Metastases (Perspective)?
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Mohammed Abd-El-Barr, MD and E. Antonio Chiocca, MD PhD Department of Neurosurgery, Brigham and Women's/ Faulkner Hospital/Dana-Farber Cancer Institute, 75 Francis Street, Boston, MA 02115 Email: [email protected] Phone: 1-617-732-6939
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Fax: 1-617-734-8342
M AN U
With improved systemic treatments of different cancers, improved radiological imaging techniques and an aging population, the incidence of brain metastases is increasing. In the early 20th century, the diagnosis of a brain metastasis was considered terminal with survivorship being measured in weeks. However, improvements in microsurgical techniques, whole brain and stereotactic radiosurgery, neuronavigation and intensive care have dramatically improved survival times in patients with brain metastases. Importantly, many of these patients are succumbing to their systemic rather than their neurological disease.
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Patients that present with brain metastases represent a heterogenous group, Increasing the difficulty for strict guidelines for optimal care 2. One of the analyses employed to try and understand which patients benefit the most from treatment for brain metastases was the recursive partitioning analysis (RPA) performed by Radiation Therapy Oncology Group (RTOG) studies 7. RPA distinguished three major classes, based on survivorship outcome. Class 1 consisted of patients that were less than 65 years of age, exhibited Karnofsky Performance Scores (KPS) of 70 or better and had good control of their systemic disease. On the other end of the spectrum, those patients with KPS less than 70 had the worse outcomes. All other patients were placed in Class 2. This partitioning system has been validated by several other studies 8. Traditionally, those patients that fall within Class 1 are offered the most aggressive treatments such as cytoreductive surgery and radiosurgery, while those in Class 3 are usually offered salvage therapies, if anything. Patients that do not belong in RPA Class 1 or 3 are the most numerous and the ones that are most difficult to figure out in terms of degree of treatment. It would be important for a clinician to have some a priori sense of which patients in Class 2 would benefit from surgery and/or other aggressive therapies. Previous studies have hinted that there might not be such a large divide between RTOG RPA Class 1 and 211. Similarly, many of the patients in the RTOG trials have not, and do not have surgery and thus there is a paucity of data of how RPA Class 2 patients do with surgery and whether or not there are preoperative characteristics that could predict which patients would benefit from surgery.
ACCEPTED MANUSCRIPT
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In this issue of WORLD NEUROSURGERY, Chaichana et al. attempt to define which preoperative characteristics are predictive of worse outcomes amongst RPA Class 2 patients undergoing surgery3. By retrospectively analyzing a large cohort of patients undergoing surgical resection for brain metastases in a large academic tertiary-care institution, they uncover some very interesting results. As expected, a majority of patients (59%) with brain metastases belong to RPA Class 2. In addition, male gender, preoperative motor deficit, preoperative cognitive deficit, the presence of multiple metastases and a volume larger than 2 cm led to a worse surgical outcome.
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The authors also develop a grading scale for these preoperative characteristics to show that worse prognosis correlates with their accumulated number. There are some important fine points that the careful reader will note. First, and in parallel to the general outcomes with brain metastases in the last 10-20 years, a majority of patients (68%) succumbed to their systemic disease while only 18% died of progressive central nervous system disease. With this in mind, this makes the results of male gender being a poor prognostic factor easier to understand, because current systemic treatments for breast cancer result in superior survival outcomes to those for prostate cancer4. The importance of the systemic disease can also be seen by noting that the average age of the patients in this study was 59.6 and the preoperative KPS 80 – thus making the systemic disease the only criterion that groups them into RPA Class 2 and not 1.
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Going beyond the RPA classes, there is a push for more individualized treatment paradigms for patients that present with brain metastases10. This includes targeted molecular therapies including tyrosine kinase inhibitors or vascular endothelial growth factor (VEGF) antibodies5,6,9 or stem cell-associated therapeutics1. In the future, it will probably be a combination of broad grading scales, such as the one put forth by Chaichana et al. and individual molecular and genetic data that will mandate which therapies patients with brain metastases receive.
1. 2.
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As with all retrospective studies, there are important limitations. By including only patients that have had surgery, there is sampling bias involved in this study. How these results apply to all patients that are seen by busy clinicians with brain metastases is not entirely clear. Nonetheless, the authors should be congratulated for providing clinicians with an important measure of which patients may or may not respond well to surgery for brain metastases.
Aboody KS, Najbauer J, Danks MK: Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther 15:739-752, 2008 Bhangoo SS, Linskey ME, Kalkanis SN, American Association of Neurologic S, Congress of Neurologic S: Evidence-based guidelines for the management of brain metastases. Neurosurg Clin N Am 22:97-104, viii, 2011
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Chaichana KL, Acharya S, Flores M, Wijesekera O, Rigamonti D, Weingart JD, et al: Identifying Better Surgical Candidates Among Recursive Partitioning Analysis Class 2 Patients who Underwent Surgery for Intracranial Metastases. World Neurosurg, 2013 Claus EB: Neurosurgical management of metastases in the central nervous system. Nat Rev Clin Oncol 9:79-86, 2012 De Braganca KC, Janjigian YY, Azzoli CG, Kris MG, Pietanza MC, Nolan CP, et al: Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer. J Neurooncol 100:443-447, 2010 Fan Y, Huang Z, Fang L, Miu L, Lin N, Gong L, et al: Chemotherapy and EGFR tyrosine kinase inhibitors for treatment of brain metastases from non-small-cell lung cancer: survival analysis in 210 patients. Onco Targets Ther 6:1789-1803, 2013 Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745-751, 1997 Gaspar LE, Scott C, Murray K, Curran W: Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 47:1001-1006, 2000 Matsumoto S, Takahashi K, Iwakawa R, Matsuno Y, Nakanishi Y, Kohno T, et al: Frequent EGFR mutations in brain metastases of lung adenocarcinoma. Int J Cancer 119:1491-1494, 2006 Olson JJ, Paleologos NA, Gaspar LE, Robinson PD, Morris RE, Ammirati M, et al: The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics. J Neurooncol 96:115-142, 2010 Regine WF, Rogozinska A, Kryscio RJ, Tibbs PA, Young AB, Patchell RA: Recursive partitioning analysis classifications I and II: applicability evaluated in a randomized trial for resected single brain metastases. Am J Clin Oncol 27:505-509, 2004
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ACCEPTED MANUSCRIPT
S1878-8750(14)00268-X
DOI:
10.1016/j.wneu.2014.03.020
Reference:
WNEU 2308
To appear in:
World Neurosurgery
Received Date: 15 February 2014 Accepted Date: 11 March 2014
Please cite this article as: Abd-El-Barr M, Antonio Chiocca E, Who Benefits from Surgery for Brain Metastases (Perspective)?, World Neurosurgery (2014), doi: 10.1016/j.wneu.2014.03.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Who Benefits from Surgery for Brain Metastases (Perspective)?
RI PT
Mohammed Abd-El-Barr, MD and E. Antonio Chiocca, MD PhD Department of Neurosurgery, Brigham and Women's/ Faulkner Hospital/Dana-Farber Cancer Institute, 75 Francis Street, Boston, MA 02115 Email: [email protected] Phone: 1-617-732-6939
SC
Fax: 1-617-734-8342
M AN U
With improved systemic treatments of different cancers, improved radiological imaging techniques and an aging population, the incidence of brain metastases is increasing. In the early 20th century, the diagnosis of a brain metastasis was considered terminal with survivorship being measured in weeks. However, improvements in microsurgical techniques, whole brain and stereotactic radiosurgery, neuronavigation and intensive care have dramatically improved survival times in patients with brain metastases. Importantly, many of these patients are succumbing to their systemic rather than their neurological disease.
AC C
EP
TE D
Patients that present with brain metastases represent a heterogenous group, Increasing the difficulty for strict guidelines for optimal care 2. One of the analyses employed to try and understand which patients benefit the most from treatment for brain metastases was the recursive partitioning analysis (RPA) performed by Radiation Therapy Oncology Group (RTOG) studies 7. RPA distinguished three major classes, based on survivorship outcome. Class 1 consisted of patients that were less than 65 years of age, exhibited Karnofsky Performance Scores (KPS) of 70 or better and had good control of their systemic disease. On the other end of the spectrum, those patients with KPS less than 70 had the worse outcomes. All other patients were placed in Class 2. This partitioning system has been validated by several other studies 8. Traditionally, those patients that fall within Class 1 are offered the most aggressive treatments such as cytoreductive surgery and radiosurgery, while those in Class 3 are usually offered salvage therapies, if anything. Patients that do not belong in RPA Class 1 or 3 are the most numerous and the ones that are most difficult to figure out in terms of degree of treatment. It would be important for a clinician to have some a priori sense of which patients in Class 2 would benefit from surgery and/or other aggressive therapies. Previous studies have hinted that there might not be such a large divide between RTOG RPA Class 1 and 211. Similarly, many of the patients in the RTOG trials have not, and do not have surgery and thus there is a paucity of data of how RPA Class 2 patients do with surgery and whether or not there are preoperative characteristics that could predict which patients would benefit from surgery.
ACCEPTED MANUSCRIPT
RI PT
In this issue of WORLD NEUROSURGERY, Chaichana et al. attempt to define which preoperative characteristics are predictive of worse outcomes amongst RPA Class 2 patients undergoing surgery3. By retrospectively analyzing a large cohort of patients undergoing surgical resection for brain metastases in a large academic tertiary-care institution, they uncover some very interesting results. As expected, a majority of patients (59%) with brain metastases belong to RPA Class 2. In addition, male gender, preoperative motor deficit, preoperative cognitive deficit, the presence of multiple metastases and a volume larger than 2 cm led to a worse surgical outcome.
M AN U
SC
The authors also develop a grading scale for these preoperative characteristics to show that worse prognosis correlates with their accumulated number. There are some important fine points that the careful reader will note. First, and in parallel to the general outcomes with brain metastases in the last 10-20 years, a majority of patients (68%) succumbed to their systemic disease while only 18% died of progressive central nervous system disease. With this in mind, this makes the results of male gender being a poor prognostic factor easier to understand, because current systemic treatments for breast cancer result in superior survival outcomes to those for prostate cancer4. The importance of the systemic disease can also be seen by noting that the average age of the patients in this study was 59.6 and the preoperative KPS 80 – thus making the systemic disease the only criterion that groups them into RPA Class 2 and not 1.
TE D
Going beyond the RPA classes, there is a push for more individualized treatment paradigms for patients that present with brain metastases10. This includes targeted molecular therapies including tyrosine kinase inhibitors or vascular endothelial growth factor (VEGF) antibodies5,6,9 or stem cell-associated therapeutics1. In the future, it will probably be a combination of broad grading scales, such as the one put forth by Chaichana et al. and individual molecular and genetic data that will mandate which therapies patients with brain metastases receive.
1. 2.
AC C
EP
As with all retrospective studies, there are important limitations. By including only patients that have had surgery, there is sampling bias involved in this study. How these results apply to all patients that are seen by busy clinicians with brain metastases is not entirely clear. Nonetheless, the authors should be congratulated for providing clinicians with an important measure of which patients may or may not respond well to surgery for brain metastases.
Aboody KS, Najbauer J, Danks MK: Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther 15:739-752, 2008 Bhangoo SS, Linskey ME, Kalkanis SN, American Association of Neurologic S, Congress of Neurologic S: Evidence-based guidelines for the management of brain metastases. Neurosurg Clin N Am 22:97-104, viii, 2011
ACCEPTED MANUSCRIPT
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M AN U
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Chaichana KL, Acharya S, Flores M, Wijesekera O, Rigamonti D, Weingart JD, et al: Identifying Better Surgical Candidates Among Recursive Partitioning Analysis Class 2 Patients who Underwent Surgery for Intracranial Metastases. World Neurosurg, 2013 Claus EB: Neurosurgical management of metastases in the central nervous system. Nat Rev Clin Oncol 9:79-86, 2012 De Braganca KC, Janjigian YY, Azzoli CG, Kris MG, Pietanza MC, Nolan CP, et al: Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer. J Neurooncol 100:443-447, 2010 Fan Y, Huang Z, Fang L, Miu L, Lin N, Gong L, et al: Chemotherapy and EGFR tyrosine kinase inhibitors for treatment of brain metastases from non-small-cell lung cancer: survival analysis in 210 patients. Onco Targets Ther 6:1789-1803, 2013 Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745-751, 1997 Gaspar LE, Scott C, Murray K, Curran W: Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 47:1001-1006, 2000 Matsumoto S, Takahashi K, Iwakawa R, Matsuno Y, Nakanishi Y, Kohno T, et al: Frequent EGFR mutations in brain metastases of lung adenocarcinoma. Int J Cancer 119:1491-1494, 2006 Olson JJ, Paleologos NA, Gaspar LE, Robinson PD, Morris RE, Ammirati M, et al: The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics. J Neurooncol 96:115-142, 2010 Regine WF, Rogozinska A, Kryscio RJ, Tibbs PA, Young AB, Patchell RA: Recursive partitioning analysis classifications I and II: applicability evaluated in a randomized trial for resected single brain metastases. Am J Clin Oncol 27:505-509, 2004
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