Downloaded from http://spcare.bmj.com/ on November 13, 2014 - Published by group.bmj.com
Case report
Prophylactic cranial irradiation: 5 years on Stephen A Ryan,1 Aoife C Lowney,2 Marie Murphy,2 Paul J Kelly,3 Derek G Power4
1
Deparment of Neurology, Mercy University Hospital, Cork, Ireland 2 Department of Palliative Medicine, Marymount University Hospice, Cork, Ireland 3 Department of Radiotherapy, Cork University Hospital, Cork, Ireland 4 Department of Medical Oncology, Mercy University Hospital, Cork, Ireland Correspondence to Dr Stephen A Ryan, Department of Neurology, Mercy University Hospital, Cork, Ireland; [email protected] Received 23 August 2012 Revised 29 November 2012 Accepted 16 December 2012 Published Online First 18 January 2013
To cite: Ryan SA, Lowney AC, Murphy M, et al. BMJ Supportive & Palliative Care 2014;4:84–86.
84
ABSTRACT With advances in cancer management, patients are living with the long-term sequelae of both cancer and its treatment. This era of cancer survivorship poses unique challenges to the interdisciplinary cancer team in terms of management and prevention of treatmentrelated toxicities. This paper describes the case of a 55-year-old patient with neurocognitive disturbance as a result of prophylactic cranial irradiation (PCI). Five years after a diagnosis of small cell lung cancer, she is now an inpatient at a specialist palliative care unit. The current evidence for PCI and for potentially modifiable risk factors for neurocognitive disturbance as a consequence of PCI is explored.
INTRODUCTION Cranial irradiation has a proven role in the treatment of primary and secondary brain tumours. Prophylactic cranial irradiation (PCI) is used for selected patients at high risk of neoplastic involvement of the central nervous system. It is most commonly employed in limited-stage small cell lung carcinoma. Although chemotherapy is the mainstay of treatment for these patients, most chemotherapeutic regimes do not adequately penetrate the bloodbrain barrier. PCI is employed in patients achieving a complete response to chemotherapy as it is associated with a decreased rate of cerebral metastases and an improvement in overall survival.1 However, cranial irradiation is associated with long-term toxicities, in particular, delayed neurocognitive disturbance. Neurotoxicity that may occur months or years following cranial irradiation is less of a concern in patients with limited life expectancy. However, for patients with small cell lung cancer (SCLC) with a 5-year overall survival of approximately 25%, the potential for late neurocognitive deficit is of greater concern. Cranial irradiation is a well-
established cause of leukoencephalopathy, and the degree of neurotoxicity correlates with total dose, dose-fractionation scheme and the volume of tissue irradiated. The risk of late neurocognitive dysfunction secondary to PCI must be weighed against the risk of neurocognitive impairments arising from the development of brain metastases in patients who do not receive PCI.2 CASE HISTORY We report the case of a 55-year-old lady who is currently under the care of the specialist palliative care services. She presented in February 2008 with limited-stage SCLC. She was initially treated with concurrent chemoradiation comprising carboplatin and etoposide with a total radiation dose to the thoracic disease of 52 Gray (Gy) in 26 fractions. This was followed in July 2008 by PCI to a dose of 36 Gy in 18 fractions. Follow-up was uneventful until 3 years later when she presented with intermittent confusion, agitation and frequent falls. On examination, she was irritable with an ataxic gait, exhibited a limited attention span, and performed poorly on formal memory testing. Bedsides these, neurocognitive assessment revealed a Montreal Cognitive Assessment Score of 12/30. MRI showed extensive white matter change throughout both cerebral hemispheres in keeping with extensive toxic leukoencephalopathy (see figure 1). DISCUSSION White matter changes as seen on T2-weighted MRI indicate disturbance of brain metabolism and vasculature. Toxic leukoencephalopathy is the clinical syndrome associated with these changes. Toxic leukoencephalopathy should be part of the differential diagnosis of any patient presenting with neurobehavioural deficits in the setting of previous cranial
Ryan SA, et al. BMJ Supportive & Palliative Care 2014;4:84–86. doi:10.1136/bmjspcare-2012-000356
Downloaded from http://spcare.bmj.com/ on November 13, 2014 - Published by group.bmj.com
Case report
Figure 1 (A) Axial T2 weighted MRI of brain showing extensive signal change throughout the cerebral white matter, see arrows. (B) Sagittal T2 weighted images illustrating extensive signal abnormality consistent with toxic leukoencephalopathy secondary to prior cranial irradiation.
irradiation. Severity of white matter change is implicated in cognitive and functional decline. White matter changes are associated with several neuropsychiatric disorders, including vascular dementia, and result in cognitive decline. Long-term sequelae following cranial irradiation include cognitive defecits and short-term memory impairment. Treatment of adverse neurological manifestations related to irradiation is limited and, therefore, attention has focused on prevention. Measures that have been employed include dose-reduction of PCI, especially in patients with established leukoariosis, employment of stereotactic radiosurgery instead of whole brain radiation therapy, hippocampal-sparing radiation techniques,3 as well as twice-daily hyperfractionation schedules.4 In terms of predictors of white matter change, age, hypertension and poor glycemic control were recently identified as possible factors contributing to more rapidly developing and severe white matter changes postcranial irradiation.5 This is of particular interest, as hypertension and glycaemic control may represent potential modifiable risk factors. Furthermore, it was recently reported that memantine, a drug normally prescribed for slowing cognitive decline in Alzheimer’s disease, can help to preserve cognitive function in cancer patients who have undergone whole brain irradiation.6 As treatment of diseases, such as limited-stage SCLC improves, the potential for long-term neurotoxicity becomes increasingly relevant. In January 2007, there were 11.7 million cancer survivors living in the USA.7 There are 2 million people living in the UK after a cancer diagnosis. This figure is projected to rise to 4 million by 2030.8 With cancer survivorship, there comes an onus on medical professionals across disciplines to address the impact of both cancer and its treatment on patients’ physical, psychological and social functioning. Despite the increased prevalence of cancer survivors, physicians are often not adequately
informed about the long-term consequences of cancer and its treatment for patients. This is particularly pertinent to palliative care services, which typically encounter patients in the latter stages of their cancer journey. The National Cancer Survivorship Initiative, a partnership between the English Department of Health and Macmillan Cancer Support, has commissioned a number of projects with a vision to improve our understanding and prevention of the consequences of cancer and its treatment.9 Our patient is now an inpatient in a specialist palliative care unit. She was admitted for symptom management and, in part, at the request of the palliative home care team, who recognised considerable carer burnout among her family members. Her care is challenging in the context of severe ataxia but poor insight into deficits as a result of neurocognitive impairment. Her clinical condition is stable, but she has been unable to self-care for 3 years. Toxic leukoencephalopathy should always be in the differential of a patient who presents with subtle neurologic deficits and a history of cranial irradiation. Where whole brain radiation is planned, the treating physician should consider prognosis and consider modifyable risk factors for leukoencephalopathy. Contributors All authors contributed to the writing and
editing of the manuscript. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1 Aupérin A, Arriagada R, Pignon JP, et al., Prophylactic Cranial Irradiation Overview Collaborative Group. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 1999;341:476–84.
Ryan SA, et al. BMJ Supportive & Palliative Care 2014;4:84–86. doi:10.1136/bmjspcare-2012-000356
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Downloaded from http://spcare.bmj.com/ on November 13, 2014 - Published by group.bmj.com
Case report 2 Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol 2004;22:157–65. 3 Marsh JC, Godbole R, Diaz AZ, et al. Sparing of the hippocampus, limbic circuit and neural stem cell compartment during partial brain radiotherapy for glioma: a dosimetric feasibility study. J Med Imaging Radiat Oncol 2011;55:442–9. 4 Wolfson AH, Bains Y, Lu J, et al. Twice-daily prophylactic cranial irradiation for patients with limited disease small-cell lung cancer with complete response to chemotherapy and consolidative radiotherapy: report of a single institutional phase II trial. Am J Clin Oncol 2001;24:290. 5 Szerlip N, Rutter C, Ram N, et al. Factors impacting volumetric white matter changes following whole brain radiation therapy. J Neurooncol 2011;103:111–19.
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6 Brown PD, Shook S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole brain radiation therapy (WBRT): First report of RTOG 0614, a placebo-controlled, double-blind, randomized trial. Int J Radiat Oncol Phys 2012;84:S1–2. 7 Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212. 8 Maher J. Consequences of cancer treatment: a new challenge for supportive and palliative care. BMJ Supportive and Palliative Care 2012;2:82–3. 9 National Cancer Survivorship Initiative: vision (2010) Department of Health, Macmillan Support, NHS Improvement. http://www.ncsi.org.uk/wp-content/uploads/ NCSI-Vision-Document.pdf. (Accessed 10.Aug.2012).
Ryan SA, et al. BMJ Supportive & Palliative Care 2014;4:84–86. doi:10.1136/bmjspcare-2012-000356
Downloaded from http://spcare.bmj.com/ on November 13, 2014 - Published by group.bmj.com
Prophylactic cranial irradiation: 5 years on Stephen A Ryan, Aoife C Lowney, Marie Murphy, Paul J Kelly and Derek G Power BMJ Support Palliat Care 2014 4: 84-86 originally published online January 18, 2013
doi: 10.1136/bmjspcare-2012-000356 Updated information and services can be found at: http://spcare.bmj.com/content/4/1/84
These include:
References Email alerting service
This article cites 8 articles, 2 of which you can access for free at: http://spcare.bmj.com/content/4/1/84#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Case report
Prophylactic cranial irradiation: 5 years on Stephen A Ryan,1 Aoife C Lowney,2 Marie Murphy,2 Paul J Kelly,3 Derek G Power4
1
Deparment of Neurology, Mercy University Hospital, Cork, Ireland 2 Department of Palliative Medicine, Marymount University Hospice, Cork, Ireland 3 Department of Radiotherapy, Cork University Hospital, Cork, Ireland 4 Department of Medical Oncology, Mercy University Hospital, Cork, Ireland Correspondence to Dr Stephen A Ryan, Department of Neurology, Mercy University Hospital, Cork, Ireland; [email protected] Received 23 August 2012 Revised 29 November 2012 Accepted 16 December 2012 Published Online First 18 January 2013
To cite: Ryan SA, Lowney AC, Murphy M, et al. BMJ Supportive & Palliative Care 2014;4:84–86.
84
ABSTRACT With advances in cancer management, patients are living with the long-term sequelae of both cancer and its treatment. This era of cancer survivorship poses unique challenges to the interdisciplinary cancer team in terms of management and prevention of treatmentrelated toxicities. This paper describes the case of a 55-year-old patient with neurocognitive disturbance as a result of prophylactic cranial irradiation (PCI). Five years after a diagnosis of small cell lung cancer, she is now an inpatient at a specialist palliative care unit. The current evidence for PCI and for potentially modifiable risk factors for neurocognitive disturbance as a consequence of PCI is explored.
INTRODUCTION Cranial irradiation has a proven role in the treatment of primary and secondary brain tumours. Prophylactic cranial irradiation (PCI) is used for selected patients at high risk of neoplastic involvement of the central nervous system. It is most commonly employed in limited-stage small cell lung carcinoma. Although chemotherapy is the mainstay of treatment for these patients, most chemotherapeutic regimes do not adequately penetrate the bloodbrain barrier. PCI is employed in patients achieving a complete response to chemotherapy as it is associated with a decreased rate of cerebral metastases and an improvement in overall survival.1 However, cranial irradiation is associated with long-term toxicities, in particular, delayed neurocognitive disturbance. Neurotoxicity that may occur months or years following cranial irradiation is less of a concern in patients with limited life expectancy. However, for patients with small cell lung cancer (SCLC) with a 5-year overall survival of approximately 25%, the potential for late neurocognitive deficit is of greater concern. Cranial irradiation is a well-
established cause of leukoencephalopathy, and the degree of neurotoxicity correlates with total dose, dose-fractionation scheme and the volume of tissue irradiated. The risk of late neurocognitive dysfunction secondary to PCI must be weighed against the risk of neurocognitive impairments arising from the development of brain metastases in patients who do not receive PCI.2 CASE HISTORY We report the case of a 55-year-old lady who is currently under the care of the specialist palliative care services. She presented in February 2008 with limited-stage SCLC. She was initially treated with concurrent chemoradiation comprising carboplatin and etoposide with a total radiation dose to the thoracic disease of 52 Gray (Gy) in 26 fractions. This was followed in July 2008 by PCI to a dose of 36 Gy in 18 fractions. Follow-up was uneventful until 3 years later when she presented with intermittent confusion, agitation and frequent falls. On examination, she was irritable with an ataxic gait, exhibited a limited attention span, and performed poorly on formal memory testing. Bedsides these, neurocognitive assessment revealed a Montreal Cognitive Assessment Score of 12/30. MRI showed extensive white matter change throughout both cerebral hemispheres in keeping with extensive toxic leukoencephalopathy (see figure 1). DISCUSSION White matter changes as seen on T2-weighted MRI indicate disturbance of brain metabolism and vasculature. Toxic leukoencephalopathy is the clinical syndrome associated with these changes. Toxic leukoencephalopathy should be part of the differential diagnosis of any patient presenting with neurobehavioural deficits in the setting of previous cranial
Ryan SA, et al. BMJ Supportive & Palliative Care 2014;4:84–86. doi:10.1136/bmjspcare-2012-000356
Downloaded from http://spcare.bmj.com/ on November 13, 2014 - Published by group.bmj.com
Case report
Figure 1 (A) Axial T2 weighted MRI of brain showing extensive signal change throughout the cerebral white matter, see arrows. (B) Sagittal T2 weighted images illustrating extensive signal abnormality consistent with toxic leukoencephalopathy secondary to prior cranial irradiation.
irradiation. Severity of white matter change is implicated in cognitive and functional decline. White matter changes are associated with several neuropsychiatric disorders, including vascular dementia, and result in cognitive decline. Long-term sequelae following cranial irradiation include cognitive defecits and short-term memory impairment. Treatment of adverse neurological manifestations related to irradiation is limited and, therefore, attention has focused on prevention. Measures that have been employed include dose-reduction of PCI, especially in patients with established leukoariosis, employment of stereotactic radiosurgery instead of whole brain radiation therapy, hippocampal-sparing radiation techniques,3 as well as twice-daily hyperfractionation schedules.4 In terms of predictors of white matter change, age, hypertension and poor glycemic control were recently identified as possible factors contributing to more rapidly developing and severe white matter changes postcranial irradiation.5 This is of particular interest, as hypertension and glycaemic control may represent potential modifiable risk factors. Furthermore, it was recently reported that memantine, a drug normally prescribed for slowing cognitive decline in Alzheimer’s disease, can help to preserve cognitive function in cancer patients who have undergone whole brain irradiation.6 As treatment of diseases, such as limited-stage SCLC improves, the potential for long-term neurotoxicity becomes increasingly relevant. In January 2007, there were 11.7 million cancer survivors living in the USA.7 There are 2 million people living in the UK after a cancer diagnosis. This figure is projected to rise to 4 million by 2030.8 With cancer survivorship, there comes an onus on medical professionals across disciplines to address the impact of both cancer and its treatment on patients’ physical, psychological and social functioning. Despite the increased prevalence of cancer survivors, physicians are often not adequately
informed about the long-term consequences of cancer and its treatment for patients. This is particularly pertinent to palliative care services, which typically encounter patients in the latter stages of their cancer journey. The National Cancer Survivorship Initiative, a partnership between the English Department of Health and Macmillan Cancer Support, has commissioned a number of projects with a vision to improve our understanding and prevention of the consequences of cancer and its treatment.9 Our patient is now an inpatient in a specialist palliative care unit. She was admitted for symptom management and, in part, at the request of the palliative home care team, who recognised considerable carer burnout among her family members. Her care is challenging in the context of severe ataxia but poor insight into deficits as a result of neurocognitive impairment. Her clinical condition is stable, but she has been unable to self-care for 3 years. Toxic leukoencephalopathy should always be in the differential of a patient who presents with subtle neurologic deficits and a history of cranial irradiation. Where whole brain radiation is planned, the treating physician should consider prognosis and consider modifyable risk factors for leukoencephalopathy. Contributors All authors contributed to the writing and
editing of the manuscript. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1 Aupérin A, Arriagada R, Pignon JP, et al., Prophylactic Cranial Irradiation Overview Collaborative Group. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 1999;341:476–84.
Ryan SA, et al. BMJ Supportive & Palliative Care 2014;4:84–86. doi:10.1136/bmjspcare-2012-000356
85
Downloaded from http://spcare.bmj.com/ on November 13, 2014 - Published by group.bmj.com
Case report 2 Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol 2004;22:157–65. 3 Marsh JC, Godbole R, Diaz AZ, et al. Sparing of the hippocampus, limbic circuit and neural stem cell compartment during partial brain radiotherapy for glioma: a dosimetric feasibility study. J Med Imaging Radiat Oncol 2011;55:442–9. 4 Wolfson AH, Bains Y, Lu J, et al. Twice-daily prophylactic cranial irradiation for patients with limited disease small-cell lung cancer with complete response to chemotherapy and consolidative radiotherapy: report of a single institutional phase II trial. Am J Clin Oncol 2001;24:290. 5 Szerlip N, Rutter C, Ram N, et al. Factors impacting volumetric white matter changes following whole brain radiation therapy. J Neurooncol 2011;103:111–19.
86
6 Brown PD, Shook S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole brain radiation therapy (WBRT): First report of RTOG 0614, a placebo-controlled, double-blind, randomized trial. Int J Radiat Oncol Phys 2012;84:S1–2. 7 Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212. 8 Maher J. Consequences of cancer treatment: a new challenge for supportive and palliative care. BMJ Supportive and Palliative Care 2012;2:82–3. 9 National Cancer Survivorship Initiative: vision (2010) Department of Health, Macmillan Support, NHS Improvement. http://www.ncsi.org.uk/wp-content/uploads/ NCSI-Vision-Document.pdf. (Accessed 10.Aug.2012).
Ryan SA, et al. BMJ Supportive & Palliative Care 2014;4:84–86. doi:10.1136/bmjspcare-2012-000356
Downloaded from http://spcare.bmj.com/ on November 13, 2014 - Published by group.bmj.com
Prophylactic cranial irradiation: 5 years on Stephen A Ryan, Aoife C Lowney, Marie Murphy, Paul J Kelly and Derek G Power BMJ Support Palliat Care 2014 4: 84-86 originally published online January 18, 2013
doi: 10.1136/bmjspcare-2012-000356 Updated information and services can be found at: http://spcare.bmj.com/content/4/1/84
These include:
References Email alerting service
This article cites 8 articles, 2 of which you can access for free at: http://spcare.bmj.com/content/4/1/84#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
