Accepted Manuscript Futility and Human Endeavor: the Treatment of Cerebral Metastases James R. Bean, MD PII:
S1878-8750(15)00804-9
DOI:
10.1016/j.wneu.2015.06.056
Reference:
WNEU 3008
To appear in:
World Neurosurgery
Received Date: 20 June 2015 Accepted Date: 22 June 2015
Please cite this article as: Bean JR, Futility and Human Endeavor: the Treatment of Cerebral Metastases, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.06.056. 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 1
PERSPECTIVE Futility and Human Endeavor: the Treatment of Cerebral Metastases
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Author: James R. Bean, MD Neurosurgical Associates Baptist Health Medical Group 1760 Nicholasville Rd. Suite B301 Lexington, KY 40503 Phone: Office 859-260-2721 Fax 859-277-8659 Cell 859-327-8166
RI PT
Key Words: cerebral metastasis, comparative effectiveness research, craniotomy, radiotherapy, stereotactic radiosurgery, existentialism
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Corresponding Author: James R. Bean, MD Neurosurgical Associates Baptist Health Medical Group 1760 Nicholasville Rd. Suite B301 Lexington, KY 40503 Phone: Office 859-260-2721 Fax 859-277-8659 Cell 859-327-8166
ACCEPTED MANUSCRIPT 2 Futility and Human Endeavor: the Treatment of Cerebral Metastases
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The treatment of cerebral metastases has evolved through several iterations of evidence. Patchell, et al published a randomized trial in 1990 that compared surgical resection of single cerebral metastases followed by whole brain radiation therapy (WBRT), to whole brain radiation therapy alone. The median survival in the surgical group was 40 weeks, while the median survival in the radiation-only group was 15 weeks. Local recurrence was 20% in the surgical group and 52% in the radiationonly group. More distant metastases in the brain were the same in both groups. Surgery was clearly superior to radiation alone. The problem, of course, and the elephant in the room, was that all surgical patients were dead before 2 years, and paradoxically the only long-term survivor was a patient in the radiation group. (4)
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Patchell, et al also confirmed in a subsequent randomized trial that postoperative radiotherapy was superior to surgery alone, with an 18% incidence of recurrent cerebral metastasis in those receiving postoperative WBRT vs. 70% recurrence in those without postoperative WBRT. (5) Stereotactic radiosurgery appeared as an alternative in the 1990’s, with a nonrandomized study by Flickinger, et al in 1994 describing “a multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis.” (1) Median survivals of a year or more were reported in nonrandomized studies. Despite these technical advances, however, patient survival remained brief, comparable to that of glioblastoma patients, because the primary systemic cancer always won. Although technical therapeutic advances were celebrated, they were but transient, hollow victories, when viewed in the context of the life and death struggle. The value of an additional month, or even multiple months of life overshadowed and diminished by an ineradicable terminal disease was and is a personal philosophical question that cost/QALY or ICER determinations cannot answer.
AC C
EP
Dr. Kimmell, et al, in their article in this issue of World Neurosurgery entitled, “Comparative Effectiveness Analysis of Treatment Options for Single Brain Metastasis”, have collated the results of 34 studies into six combinations of what have become standard therapeutic approaches to cerebral metastases: surgery, SRS (stereotactic radiosurgery), WBRT, surgery+SRS, surgery+WBRT, and SRS+WBRT. The results of treatment were reviewed and compared in terms of efficacy (median survival and local or distant recurrence), cost based on 2011 data published in the Healthcare Cost and Utilization Project (HCUP) by the federal Agency for Healthcare Research and Quality (AHRQ), and quality of life (QOL) based generally on the Karnofsky Performance Score (KPS). The authors noted that few of the reviewed trials were randomized studies, and that the purpose of their investigation was to “provide semi-quantitative information…regarding the differential efficacy, QOL, and cost among alternate strategies for BM (brain metastasis) used individually or in combination,” not “to offer treatment recommendations or to evaluate the level and quality of extant evidence.” The aim was to use a comparative effectiveness analysis for an evidence-based comparison of treatments summarized concisely in graphic tables to “approach the evidence from a patient-centered perspective” and
ACCEPTED MANUSCRIPT 3 allow decision-making “in the practical context in which physicians interpret data on a daily basis.”
SC
RI PT
The study concluded that surgery+SRS was the most efficacious, with the longest median survival (62 weeks) and the lowest local recurrence rate (20%), but at the expense of the highest median cost ($48,496). The highest quality of life scores occurred in the 3 SRS categories. Surgery and SRS, either alone or combined with WBRT all clustered around a 47 – 50 week median survival. WBRT scored the lowest on cost ($13,671), but the least effective in survival (29 weeks), recurrence (57%) and quality of life (0.24 QALYs). There was undoubtedly a selection bias in those receiving WBRT alone in nonrandomized studies, reflected in the low effectiveness scores; characteristics of the tumor, underlying malignant disease, general health, or other factors may have made them ineligible for surgery or SRS, and less likely to survive.
M AN U
The eight tables summarizing the study results make a quick comparison of the six pooled categories of treatment of the different options practical and useful in a clinical setting. Survival did not seem to correlate directly with tumor type, rather varied more directly with preoperative Karnofsky score, age, number of brain lesions, and most intuitively important, control of extracranial disease. The study succinctly summarized the contemporary management of one of neurosurgery’s most frustrating problems.
EP
TE D
Patients with cerebral metastases and glioblastomas share a common quandary and a similar fate. Metastases differ from glioblastomas primarily because the source is outside the brain, and extracranial metastases principally determine the length of survival. Metastases resemble glioblastomas in that death occurs by progression of disease beyond the margins of surgical treatment, which cannot be cured by resection or wide radiotherapy. For both conditions, treatment, with rare exceptions, temporarily delays an inevitable demise.
AC C
In the August 2004 Journal of Neurosurgery, Patrick Kelly wrote an editorial response to an article on intraoperative stereotactic guidance using MR spectroscopy imaging. His editorial was entitled “Technology in the resection of gliomas and the definition of madness”. His opening paragraph summarized the futility he recognized during his career pursuing stereotactic volumetric glioma resection and the quest of neurosurgery in general to conquer cerebral gliomas by ever more technically complex methods to define the margins of tumor and achieve a cure by complete surgical resection. He wrote, “Someone once defined madness as doing the same thing over and over again, expecting a different result. Year after year we develop new technological methods…that enable us to resect larger portions of a glioma more accurately. Despite these efforts, patients continue to die of recurrent disease.” (3) Rather than extol another technical advance in a futile attempt to thwart disease by local extirpation, he reversed the telescope to view the problem from a distance with a philosophical musing.
ACCEPTED MANUSCRIPT 4
RI PT
At the end of his editorial, Dr. Kelly wrote, “We must continue to develop new and less invasive methods to increase the efficacy, efficiency, and safety of our procedures. That is what we, as neurosurgeons, do. Nonetheless, glioma represents a complex disease that must be understood and dealt with on a cellular level, if we are to see a significant improvement in survival or cure. In the meantime, we pursue the madness of our art.” (3)
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The authors of the article referenced by Dr. Kelly replied with an existentialist reflection: “Dr. Kelly has written a brilliant essay about the apparently futile struggle of neurosurgeons against the biology of nature…Why do we ceaselessly try to resect gliomas as radically as we can, knowing that we cannot cure our patients who eventually succumb to their disease? Do we not resemble a modern Sisyphus who again and again tries to fulfill his task while fully aware of his absurd situation? ... Maybe it is as Albert Camus once wrote, ‘…the fight itself suffices to fill [the] heart of man. One must imagine Sisyphus happy.” (2) That reply probably cannot be improved upon.
EP
References:
TE D
We apply what we can; we do what we know. But we don’t know enough. The real answer lies not in comparative effectiveness studies of current therapies or technological improvements in surgical and radiotherapeutic techniques. Neurooncology begs for a paradigm shift that eliminates the need for better tumor margin delineation, computerized volumetric resection, or stereotactic 3D planning; one that renders surgery and radiation obsolete. The value of technical advances in local tumor extirpation or destruction is marginal, when fate is only delayed and not finally cheated of her victim. A disruptive innovation seems to be rising slowly on the horizon. The real hope lies in immunotherapy, or conceptually similar systemic solutions, wherein the body’s own surveillance system becomes the living executor of tumor cell recognition and demolition, and no tumor cell escapes detection.
AC C
1. Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, Goodman ML, Shaw EG, Hudgin WR, Weiner R, Harsh GR, Sneed PK, Larson DA: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. International Journal of Radiation Oncology*Biology*Physics 28: 797 – 802, 1994. 2. Ganslandt O, Fahlbusch R, Nimsky C, Stadlbauer A, Moser E: Response, a happy Sisyphus. Journal of Neurosurgery 101: 286, 2004. 3. Kelly, PJ: Technology in the resection of gliomas and the definition of madness. Journal of Neurosurgery 101: 284 – 286, 2004. 4. Patchell RA, Tibbs PA, Walsh JW, Dempsey, RJ, Maruyama Y, Kryscio RJ, Markesbery WR, Macdonald JS, Young B: A randomized trial of surgery in the treatment of single metastases to the brain. NEJM 322: 494 – 500, 1990.
ACCEPTED MANUSCRIPT 5
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5. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, Markesbery, WR, Foon KA, Young B: Postoperative radiotherapy in the treatment of single metastases to the brain. JAMA 280: 1485 – 1489, 1998.
ACCEPTED MANUSCRIPT
PERSPECTIVE Futility and Human Endeavor: the Treatment of Cerebral Metastases
AC C
EP
TE D
M AN U
SC
RI PT
Highlights: 1. Treatment of single brain metastasis 2. Comparative effective analysis 3. Comparing surgical resection, stereotactic radiosurgery (SRS), and whole brain radiation (WBRT), and combinations of treatments 4. Comparing outcomes of efficacy (survival, tumor recurrence), cost, and quality of life (Karnofsky scale) among 6 different treatment choices 5. Similarities between the technical limits of surgery and radiation for glioma and cerebral metastasis 6. Consideration of the perspective of futility in treatment
S1878-8750(15)00804-9
DOI:
10.1016/j.wneu.2015.06.056
Reference:
WNEU 3008
To appear in:
World Neurosurgery
Received Date: 20 June 2015 Accepted Date: 22 June 2015
Please cite this article as: Bean JR, Futility and Human Endeavor: the Treatment of Cerebral Metastases, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.06.056. 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 1
PERSPECTIVE Futility and Human Endeavor: the Treatment of Cerebral Metastases
SC
M AN U
Author: James R. Bean, MD Neurosurgical Associates Baptist Health Medical Group 1760 Nicholasville Rd. Suite B301 Lexington, KY 40503 Phone: Office 859-260-2721 Fax 859-277-8659 Cell 859-327-8166
RI PT
Key Words: cerebral metastasis, comparative effectiveness research, craniotomy, radiotherapy, stereotactic radiosurgery, existentialism
AC C
EP
TE D
Corresponding Author: James R. Bean, MD Neurosurgical Associates Baptist Health Medical Group 1760 Nicholasville Rd. Suite B301 Lexington, KY 40503 Phone: Office 859-260-2721 Fax 859-277-8659 Cell 859-327-8166
ACCEPTED MANUSCRIPT 2 Futility and Human Endeavor: the Treatment of Cerebral Metastases
SC
RI PT
The treatment of cerebral metastases has evolved through several iterations of evidence. Patchell, et al published a randomized trial in 1990 that compared surgical resection of single cerebral metastases followed by whole brain radiation therapy (WBRT), to whole brain radiation therapy alone. The median survival in the surgical group was 40 weeks, while the median survival in the radiation-only group was 15 weeks. Local recurrence was 20% in the surgical group and 52% in the radiationonly group. More distant metastases in the brain were the same in both groups. Surgery was clearly superior to radiation alone. The problem, of course, and the elephant in the room, was that all surgical patients were dead before 2 years, and paradoxically the only long-term survivor was a patient in the radiation group. (4)
TE D
M AN U
Patchell, et al also confirmed in a subsequent randomized trial that postoperative radiotherapy was superior to surgery alone, with an 18% incidence of recurrent cerebral metastasis in those receiving postoperative WBRT vs. 70% recurrence in those without postoperative WBRT. (5) Stereotactic radiosurgery appeared as an alternative in the 1990’s, with a nonrandomized study by Flickinger, et al in 1994 describing “a multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis.” (1) Median survivals of a year or more were reported in nonrandomized studies. Despite these technical advances, however, patient survival remained brief, comparable to that of glioblastoma patients, because the primary systemic cancer always won. Although technical therapeutic advances were celebrated, they were but transient, hollow victories, when viewed in the context of the life and death struggle. The value of an additional month, or even multiple months of life overshadowed and diminished by an ineradicable terminal disease was and is a personal philosophical question that cost/QALY or ICER determinations cannot answer.
AC C
EP
Dr. Kimmell, et al, in their article in this issue of World Neurosurgery entitled, “Comparative Effectiveness Analysis of Treatment Options for Single Brain Metastasis”, have collated the results of 34 studies into six combinations of what have become standard therapeutic approaches to cerebral metastases: surgery, SRS (stereotactic radiosurgery), WBRT, surgery+SRS, surgery+WBRT, and SRS+WBRT. The results of treatment were reviewed and compared in terms of efficacy (median survival and local or distant recurrence), cost based on 2011 data published in the Healthcare Cost and Utilization Project (HCUP) by the federal Agency for Healthcare Research and Quality (AHRQ), and quality of life (QOL) based generally on the Karnofsky Performance Score (KPS). The authors noted that few of the reviewed trials were randomized studies, and that the purpose of their investigation was to “provide semi-quantitative information…regarding the differential efficacy, QOL, and cost among alternate strategies for BM (brain metastasis) used individually or in combination,” not “to offer treatment recommendations or to evaluate the level and quality of extant evidence.” The aim was to use a comparative effectiveness analysis for an evidence-based comparison of treatments summarized concisely in graphic tables to “approach the evidence from a patient-centered perspective” and
ACCEPTED MANUSCRIPT 3 allow decision-making “in the practical context in which physicians interpret data on a daily basis.”
SC
RI PT
The study concluded that surgery+SRS was the most efficacious, with the longest median survival (62 weeks) and the lowest local recurrence rate (20%), but at the expense of the highest median cost ($48,496). The highest quality of life scores occurred in the 3 SRS categories. Surgery and SRS, either alone or combined with WBRT all clustered around a 47 – 50 week median survival. WBRT scored the lowest on cost ($13,671), but the least effective in survival (29 weeks), recurrence (57%) and quality of life (0.24 QALYs). There was undoubtedly a selection bias in those receiving WBRT alone in nonrandomized studies, reflected in the low effectiveness scores; characteristics of the tumor, underlying malignant disease, general health, or other factors may have made them ineligible for surgery or SRS, and less likely to survive.
M AN U
The eight tables summarizing the study results make a quick comparison of the six pooled categories of treatment of the different options practical and useful in a clinical setting. Survival did not seem to correlate directly with tumor type, rather varied more directly with preoperative Karnofsky score, age, number of brain lesions, and most intuitively important, control of extracranial disease. The study succinctly summarized the contemporary management of one of neurosurgery’s most frustrating problems.
EP
TE D
Patients with cerebral metastases and glioblastomas share a common quandary and a similar fate. Metastases differ from glioblastomas primarily because the source is outside the brain, and extracranial metastases principally determine the length of survival. Metastases resemble glioblastomas in that death occurs by progression of disease beyond the margins of surgical treatment, which cannot be cured by resection or wide radiotherapy. For both conditions, treatment, with rare exceptions, temporarily delays an inevitable demise.
AC C
In the August 2004 Journal of Neurosurgery, Patrick Kelly wrote an editorial response to an article on intraoperative stereotactic guidance using MR spectroscopy imaging. His editorial was entitled “Technology in the resection of gliomas and the definition of madness”. His opening paragraph summarized the futility he recognized during his career pursuing stereotactic volumetric glioma resection and the quest of neurosurgery in general to conquer cerebral gliomas by ever more technically complex methods to define the margins of tumor and achieve a cure by complete surgical resection. He wrote, “Someone once defined madness as doing the same thing over and over again, expecting a different result. Year after year we develop new technological methods…that enable us to resect larger portions of a glioma more accurately. Despite these efforts, patients continue to die of recurrent disease.” (3) Rather than extol another technical advance in a futile attempt to thwart disease by local extirpation, he reversed the telescope to view the problem from a distance with a philosophical musing.
ACCEPTED MANUSCRIPT 4
RI PT
At the end of his editorial, Dr. Kelly wrote, “We must continue to develop new and less invasive methods to increase the efficacy, efficiency, and safety of our procedures. That is what we, as neurosurgeons, do. Nonetheless, glioma represents a complex disease that must be understood and dealt with on a cellular level, if we are to see a significant improvement in survival or cure. In the meantime, we pursue the madness of our art.” (3)
M AN U
SC
The authors of the article referenced by Dr. Kelly replied with an existentialist reflection: “Dr. Kelly has written a brilliant essay about the apparently futile struggle of neurosurgeons against the biology of nature…Why do we ceaselessly try to resect gliomas as radically as we can, knowing that we cannot cure our patients who eventually succumb to their disease? Do we not resemble a modern Sisyphus who again and again tries to fulfill his task while fully aware of his absurd situation? ... Maybe it is as Albert Camus once wrote, ‘…the fight itself suffices to fill [the] heart of man. One must imagine Sisyphus happy.” (2) That reply probably cannot be improved upon.
EP
References:
TE D
We apply what we can; we do what we know. But we don’t know enough. The real answer lies not in comparative effectiveness studies of current therapies or technological improvements in surgical and radiotherapeutic techniques. Neurooncology begs for a paradigm shift that eliminates the need for better tumor margin delineation, computerized volumetric resection, or stereotactic 3D planning; one that renders surgery and radiation obsolete. The value of technical advances in local tumor extirpation or destruction is marginal, when fate is only delayed and not finally cheated of her victim. A disruptive innovation seems to be rising slowly on the horizon. The real hope lies in immunotherapy, or conceptually similar systemic solutions, wherein the body’s own surveillance system becomes the living executor of tumor cell recognition and demolition, and no tumor cell escapes detection.
AC C
1. Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, Goodman ML, Shaw EG, Hudgin WR, Weiner R, Harsh GR, Sneed PK, Larson DA: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. International Journal of Radiation Oncology*Biology*Physics 28: 797 – 802, 1994. 2. Ganslandt O, Fahlbusch R, Nimsky C, Stadlbauer A, Moser E: Response, a happy Sisyphus. Journal of Neurosurgery 101: 286, 2004. 3. Kelly, PJ: Technology in the resection of gliomas and the definition of madness. Journal of Neurosurgery 101: 284 – 286, 2004. 4. Patchell RA, Tibbs PA, Walsh JW, Dempsey, RJ, Maruyama Y, Kryscio RJ, Markesbery WR, Macdonald JS, Young B: A randomized trial of surgery in the treatment of single metastases to the brain. NEJM 322: 494 – 500, 1990.
ACCEPTED MANUSCRIPT 5
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EP
TE D
M AN U
SC
RI PT
5. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, Markesbery, WR, Foon KA, Young B: Postoperative radiotherapy in the treatment of single metastases to the brain. JAMA 280: 1485 – 1489, 1998.
ACCEPTED MANUSCRIPT
PERSPECTIVE Futility and Human Endeavor: the Treatment of Cerebral Metastases
AC C
EP
TE D
M AN U
SC
RI PT
Highlights: 1. Treatment of single brain metastasis 2. Comparative effective analysis 3. Comparing surgical resection, stereotactic radiosurgery (SRS), and whole brain radiation (WBRT), and combinations of treatments 4. Comparing outcomes of efficacy (survival, tumor recurrence), cost, and quality of life (Karnofsky scale) among 6 different treatment choices 5. Similarities between the technical limits of surgery and radiation for glioma and cerebral metastasis 6. Consideration of the perspective of futility in treatment
