Intracerebral metastases medical therapy: Difference between revisions

Jump to navigation Jump to search
No edit summary
 
(37 intermediate revisions by 2 users not shown)
Line 2: Line 2:
{{Intracerebral metastases}}
{{Intracerebral metastases}}
{{CMG}}{{AE}}{{SR}}
{{CMG}}{{AE}}{{SR}}


==Overview==
==Overview==
The optimal therapy for intracerebral metastases depends on the number, size, and location of the metastatic lesions. The various treatment options for intracerebral metastases include symptomatic treatment ([[corticosteroids]] and [[anticonvulsants]]), [[radiotherapy|whole brain radiotherapy]], [[chemotherapy]], [[stereotactic radiosurgery]], and [[surgery]].<ref name=historicalperspectiveofintracerebralmetastases>{{Cite journal| author = [[Andrew B. Lassman]] & [[Lisa M. DeAngelis]] | title = Brain metastases | journal = [[Neurologic clinics]] | volume = 21 | issue = 1 | pages = 1–23 | year = 2003 | month = February | pmid = 12690643}}</ref><ref name="Khuntia2015">{{cite journal|last1=Khuntia|first1=Deepak|title=Contemporary Review of the Management of Brain Metastasis with Radiation|journal=Advances in Neuroscience|volume=2015|year=2015|pages=1–13|issn=2356-6787|doi=10.1155/2015/372856}}</ref><ref name=symptomaticrxofbrainmets2>Symptomatic treatment of brain metastasis. Wikipedia 2015. https://en.wikipedia.org/wiki/Brain_metastasis. Accessed on November 10, 2015</ref><ref name=radiationforbrainmets1>Radiation therapy for intracerebral metastases. Canadian cancer institute 2015. http://www.cancer.ca/en/cancer-information/cancer-type/metastatic-cancer/brain-metastases/treatment/?region=on. Accessed on November 13, 2015</ref><ref name=symptomaticrxofbrainmetastasis1>Symptomatic treatment of brain metastases. Dr Bruno Di Muzio and Dr Trent Orton et al. Radiopaedia 2015. http://radiopaedia.org/articles/brain-metastases. Accessed on November 9, 2015</ref>


==Medical Therapy==
==Medical Therapy==
Line 12: Line 12:


{{familytree/start |summary=Treatment for brain metatases}}
{{familytree/start |summary=Treatment for brain metatases}}
{{familytree |boxstyle=background: #F5F5F5;| | | | | | | | | A01 | | | | |A01=<div style="width: 9em; padding:0.2em;">'''Treatment for brain metatases'''</div>}}
{{familytree |boxstyle=background: #DCDCDC;| | | | | | | | | A01 | | | | |A01=<div style="width: 8em; padding:0.2em;">'''Treatment for brain metatases'''</div>}}
{{familytree |boxstyle=background: #F5F5F5;| | | |,|-|-|-|-|-|^|-|-|-|-|-|.| | | | | | | }}
{{familytree |boxstyle=background: #DCDCDC;| | | |,|-|-|-|-|-|^|-|-|-|-|-|.| | | | | | | }}
{{familytree |boxstyle=background: #F5F5F5;| | | B01 | | | | | | | | | | B02 | | | | |B01=<div style="width: 9em; padding:0.2em;">'''Symptomatic treatment'''</div>|B02=<div style="width: 9em; padding:0.2em;">'''Definitive treatment'''</div>}}
{{familytree |boxstyle=background: #DCDCDC;| | | B01 | | | | | | | | | | B02 | | | | |B01=<div style="width: 8em; padding:0.2em;">'''Symptomatic treatment'''</div>|B02=<div style="width: 8em; padding:0.2em;">'''Definitive treatment'''</div>}}
{{familytree |boxstyle=background: #F5F5F5;| |,|-|^|-|.| | | |,|-|-|-|v|-|^|-|v|-|-|-|.| | | }}
{{familytree |boxstyle=background: #DCDCDC;| |,|-|^|-|.| | | |,|-|-|-|v|-|^|-|v|-|-|-|.| | | }}
{{familytree |boxstyle=background: #F5F5F5;| D01 | | D02 | | D03 | | D04 | | D05 | | D06 | |D01=<div style="width: 9em; padding:0.2em;">'''Corticosteroids''' </div>|D02=<div style="width: 9em; padding:0.2em;">'''Anticonvulsants'''</div>|D03=<div style="width: 9em; padding:0.2em;">'''Whole brain radiotherapy'''</div>|D04=<div style="width: 9em; padding:0.2em;">'''Surgery'''</div>|D05=<div style="width: 9em; padding:0.2em;">'''Stereotactic radiosurgery'''</div>|D06=<div style="width: 9em; padding:0.2em;">'''Chemotherapy'''</div>}}
{{familytree |boxstyle=background: #DCDCDC;| D01 | | D02 | | D03 | | D04 | | D05 | | D06 | |D01=<div style="width: 8em; padding:0.2em;">'''Corticosteroids''' </div>|D02=<div style="width: 8em; padding:0.2em;">'''Anticonvulsants'''</div>|D03=<div style="width: 8em; padding:0.2em;">'''Whole brain radiotherapy'''</div>|D04=<div style="width: 8em; padding:0.2em;">'''Surgery'''</div>|D05=<div style="width: 8em; padding:0.2em;">'''Stereotactic radiosurgery'''</div>|D06=<div style="width: 8em; padding:0.2em;">'''Chemotherapy'''</div>}}
{{familytree/end}}
{{familytree/end}}


===Symptomatic Treatment===
===Symptomatic Treatment===
*[[Corticosteroid]] therapy is essential for all patients with brain metastases, as it prevents the development of cerebral edema, as well as treating other neurological symptoms such as [[headaches]], [[cognition|cognitive dysfunction]], and [[emesis]]. [[Dexamethasone]] is the corticosteroid of choice.<ref name="Khuntia2015">{{cite journal|last1=Khuntia|first1=Deepak|title=Contemporary Review of the Management of Brain Metastasis with Radiation|journal=Advances in Neuroscience|volume=2015|year=2015|pages=1–13|issn=2356-6787|doi=10.1155/2015/372856}}</ref><ref name=symptomaticrxofbrainmets2>Symptomatic treatment of brain metastasis. Wikipedia 2015. https://en.wikipedia.org/wiki/Brain_metastasis. Accessed on November 10, 2015</ref>
*[[Corticosteroid]] therapy is essential for all patients with intracerebral metastases, as it prevents the development of cerebral [[edema]], as well as treating other neurological symptoms such as [[headaches]], [[cognition|cognitive dysfunction]], and [[emesis]]. [[Dexamethasone]] is the corticosteroid of choice.<ref name="Khuntia2015">{{cite journal|last1=Khuntia|first1=Deepak|title=Contemporary Review of the Management of Brain Metastasis with Radiation|journal=Advances in Neuroscience|volume=2015|year=2015|pages=1–13|issn=2356-6787|doi=10.1155/2015/372856}}</ref><ref name=symptomaticrxofbrainmets2>Symptomatic treatment of brain metastasis. Wikipedia 2015. https://en.wikipedia.org/wiki/Brain_metastasis. Accessed on November 10, 2015</ref>
*[[Anticonvulsants]] should be used in patients with brain metastases who experience seizures, as there is a risk of status epilepticus and death. [[Phenytoin]] is the most commonly used drug, but [[valproic acid]] and other anticonvulsants can also be used. Newer anticonvulsants have the advantage of fewer toxic side effects.<ref name=symptomaticrxofbrainmets2>Symptomatic treatment of brain metastasis. Wikipedia 2015. https://en.wikipedia.org/wiki/Brain_metastasis. Accessed on November 10, 2015</ref><ref name=symptomaticrxofbrainmetastasis1>Symptomatic treatment of brain metastases. Dr Bruno Di Muzio and Dr Trent Orton et al. Radiopaedia 2015. http://radiopaedia.org/articles/brain-metastases. Accessed on November 9, 2015</ref>
*[[Anticonvulsants]] should be used in patients with intracerebral metastases who experience seizures, as there is a risk of status epilepticus and death. [[Phenytoin]] is the most commonly used drug, but [[valproic acid]] and other anticonvulsants can also be used. Newer anticonvulsants have the advantage of fewer toxic side effects.<ref name=symptomaticrxofbrainmets2>Symptomatic treatment of brain metastasis. Wikipedia 2015. https://en.wikipedia.org/wiki/Brain_metastasis. Accessed on November 10, 2015</ref><ref name=symptomaticrxofbrainmetastasis1>Symptomatic treatment of brain metastases. Dr Bruno Di Muzio and Dr Trent Orton et al. Radiopaedia 2015. http://radiopaedia.org/articles/brain-metastases. Accessed on November 9, 2015</ref>
*Hyperosmolar agents (i.e., [[mannitol]]) can be given to reduce intracranial pressure.<ref name=symptomaticrxofbrainmetastasis1>Symptomatic treatment of brain metastases. Dr Bruno Di Muzio and Dr Trent Orton et al. Radiopaedia 2015. http://radiopaedia.org/articles/brain-metastases. Accessed on November 9, 2015</ref>
*Hyperosmolar agents (i.e., [[mannitol]]) can be given to reduce intracranial pressure.<ref name=symptomaticrxofbrainmetastasis1>Symptomatic treatment of brain metastases. Dr Bruno Di Muzio and Dr Trent Orton et al. Radiopaedia 2015. http://radiopaedia.org/articles/brain-metastases. Accessed on November 9, 2015</ref>
*Recently, [[methylphenidate]] and [[donepezil]] have been used to improve cognition, mood, and quality of life.
*Recently, [[methylphenidate]] and [[donepezil]] have been used to improve cognition, mood, and quality of life.


===Therapeutic Treatment===
===Radiation Therapy===
====Radiation Therapy====
*The most widely used treatment for patients with multiple intracerebral metastases is [[external beam radiotherapy|whole brain external beam radiotherapy (WBRT)]].<ref name="Khuntia2015">{{cite journal|last1=Khuntia|first1=Deepak|title=Contemporary Review of the Management of Brain Metastasis with Radiation|journal=Advances in Neuroscience|volume=2015|year=2015|pages=1–13|issn=2356-6787|doi=10.1155/2015/372856}}</ref>
*The most widely used treatment for patients with multiple brain metastases is [[external beam radiotherapy|whole brain external beam radiotherapy (WBRT)]].<ref name="Khuntia2015">{{cite journal|last1=Khuntia|first1=Deepak|title=Contemporary Review of the Management of Brain Metastasis with Radiation|journal=Advances in Neuroscience|volume=2015|year=2015|pages=1–13|issn=2356-6787|doi=10.1155/2015/372856}}</ref>
*The role of radiation therapy in treatment of intracerebral metastases include:<ref name=radiationforbrainmets1>Radiation therapy for intracerebral metastases. Canadian cancer institute 2015. http://www.cancer.ca/en/cancer-information/cancer-type/metastatic-cancer/brain-metastases/treatment/?region=on. Accessed on November 13, 2015</ref>
*Stereotactic radiosurgery is done for smaller masses.
:*Control the growth of the tumor(s)
*The appropriate use of WBRT can provide rapid improvements of many neurologic symptoms, improve quality of life, and may be especially beneficial in patients whose brain metastases are surgically inaccessible or when other medical considerations remove surgery from the list of appropriate options [32–34]. The use of adjuvant WBRT, following resection or radiosurgery has been proven to be effective in terms of improving local control of brain metastases, and, furthermore, the likelihood of neurological death is decreased based on a randomized trial.
:*Control neurological symptoms, such as [[headaches]] or [[seizures]]
*In patients who have brain metastases that impinge upon eloquent areas or are too large, numerous, disseminated for surgery or [[radiosurgery]], or in patients that performance status does not allow for more aggressive therapy, whole brain external beam radiotherapy alone remains the treatment of choice and provides effective symptom relief. Response rates following whole brain external beam radiotherapy vary with complete or partial responses in more than 60% of patients.
*Whole brain [[radiation therapy]] (WBRT) is a type of [[external beam radiation therapy]]. Indications for WBRT include:<ref name=radiationforbrainmets1>Radiation therapy for intracerebral metastases. Canadian cancer institute 2015. http://www.cancer.ca/en/cancer-information/cancer-type/metastatic-cancer/brain-metastases/treatment/?region=on. Accessed on November 13, 2015</ref>
 
{| style="border: 0px; font-size: 90%; margin: 3px; width:1000px align=center"
|valign=top|
|+
! style="background: #4479BA; width: 800px;" | {{fontcolor|#FFF|Indication}}
! style="background: #4479BA; width: 800px;" | {{fontcolor|#FFF|Explanation}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align=center |
Multiple brain metastases
| style="padding: 5px 5px; background: #F5F5F5;" |
*More than 3 metastatic brain tumors or in people with poor performance status
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" align=center|
Single brain metastasis that cannot be removed by surgery
| style="padding: 5px 5px; background: #F5F5F5;" |
*Brain tumors are in an inaccesible area or if the affected area would be damaged by surgery
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" align=center|
Post surgical removal of a single brain metastasis
| style="padding: 5px 5px; background: #F5F5F5;" |
*To destroy remnant cancer cells post surgery and reduce the chance of recurrence
|}
 
*One major concern with the use of whole brain radiotherapy is the risk of neurocognitive deficits, particularly short-term memory loss.<ref name="OwenSouhami2014">{{cite journal|last1=Owen|first1=Scott|last2=Souhami|first2=Luis|title=The Management of Brain Metastases in Non-Small Cell Lung Cancer|journal=Frontiers in Oncology|volume=4|year=2014|issn=2234-943X|doi=10.3389/fonc.2014.00248}}</ref>
 
===Chemotherapy===
*[[Chemotherapy]] is the use of cytotoxic drugs that circulate throughout the body and destroy cancer cells.<ref name=chemoforbrainmets1>Chemotherapy for intracerebral metastases. Canadian cancer institute 2015. http://www.cancer.ca/en/cancer-information/cancer-type/metastatic-cancer/brain-metastases/treatment/?region=on. Accessed on November 13, 2015</ref>
*Chemotherapy may help shrink brain metastases and improve symptoms.
*Due to the failure of most drugs to cross the intact blood–brain barrier (BBB), the role of chemotherapy in the treatment of intracerebral metastases has been viewed critically. Chemotherapy drugs are generally large (> 150 kDa), ionized, hydrophilic, and often protein-bound and therefore, ill-suited to penetrate the tight-junctions, electrochemical barrier, astrocyte foot-processes, and highly regulated transmembrane transport proteins of the central nervous system’s endothelial vasculature.
*However, the effects of the blood-brain barrier may be over-estimated. First, there is evidence that the blood-brain barrier of intracerebral metastases is disrupted, as evidenced by the presence of peritumoral edema and the accumulation of contrast media during computed tomography or magnetic resonance assessments. Second, there is evidence of intracranial tumor response, even to drugs that in healthy systems have little central nervous system penetration.
*The response rates of intracerebral metastases to platinum-based agents ([[cisplatin]]) in seven clinical trials of treatment-naive non-small cell lung cancer patients were similar to those achieved extra-cranially, ranging from 30 to 50%. However, the median survival time remained only 5–8 months in most cases. However, three trials using [[temozolomide]] achieved a response rate of only 0–10%, suggesting that the selection of chemotherapy drugs should be based mainly on their established anti-tumor activity to extracranial sites, and not on considerations of blood-brain barrier penetrance.
*Responsiveness of brain metastases to chemotherapy depends on how sensitive the primary cancer is to chemotherapy drugs (chemosensitivity). For example, chemotherapy may be used to treat [[lung cancer]], [[breast cancer]], or [[melanoma]] that has spread to the brain.
*The chemotherapy drugs used depend on the type of primary tumor. The drugs, dose, and schedule will vary for each individual.


==Gallery==
==Gallery==
<gallery>
<gallery>
Image:Whole brain external beam radiotherapy 1.PNG|<sub>Hippocampal sparing whole brain radiotherapy plan showing treatment of the whole brain to 30 Gy while sparing the hippocampi from high doses of radiation which is receiving less than 10 Gy mean dose. Furthermore, it is also possible to dose escalate the gross disease simultaneously (courtesy of Wolfgang Tomé, Ph.D.).<ref name="Khuntia2015">{{cite journal|last1=Khuntia|first1=Deepak|title=Contemporary Review of the Management of Brain Metastasis with Radiation|journal=Advances in Neuroscience|volume=2015|year=2015|pages=1–13|issn=2356-6787|doi=10.1155/2015/372856}}</ref></sub>
Image:Whole brain external beam radiotherapy 1.PNG|<sub>Hippocampal sparing whole brain radiotherapy plan showing treatment of the whole brain to 30 Gy while sparing the hippocampi from high doses of radiation which is receiving less than 10 Gy mean dose. Furthermore, it is also possible to dose escalate the gross disease simultaneously (courtesy of Wolfgang Tomé, Ph.D.).<ref name="Khuntia2015">{{cite journal|last1=Khuntia|first1=Deepak|title=Contemporary Review of the Management of Brain Metastasis with Radiation|journal=Advances in Neuroscience|volume=2015|year=2015|pages=1–13|issn=2356-6787|doi=10.1155/2015/372856}}</ref></sub>


</gallery>
</gallery>

Latest revision as of 20:11, 23 November 2015

Intracerebral metastases Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Intracerebral Metastases from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Staging

History and Symptoms

Physical Examination

Laboratory Findings

Chest X Ray

CT

MRI

Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Intracerebral metastases medical therapy On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Intracerebral metastases medical therapy

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Intracerebral metastases medical therapy

CDC on Intracerebral metastases medical therapy

Intracerebral metastases medical therapy in the news

Blogs on Intracerebral metastases medical therapy

Directions to Hospitals Treating Intracerebral metastases

Risk calculators and risk factors for Intracerebral metastases medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Overview

The optimal therapy for intracerebral metastases depends on the number, size, and location of the metastatic lesions. The various treatment options for intracerebral metastases include symptomatic treatment (corticosteroids and anticonvulsants), whole brain radiotherapy, chemotherapy, stereotactic radiosurgery, and surgery.[1][2][3][4][5]

Medical Therapy

The treatment options for intracerebral metastases include the following:[1]


 
 
 
 
 
 
 
 
Treatment for brain metatases
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptomatic treatment
 
 
 
 
 
 
 
 
 
Definitive treatment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Corticosteroids
 
Anticonvulsants
 
Whole brain radiotherapy
 
Surgery
 
Stereotactic radiosurgery
 
Chemotherapy
 

Symptomatic Treatment

  • Corticosteroid therapy is essential for all patients with intracerebral metastases, as it prevents the development of cerebral edema, as well as treating other neurological symptoms such as headaches, cognitive dysfunction, and emesis. Dexamethasone is the corticosteroid of choice.[2][3]
  • Anticonvulsants should be used in patients with intracerebral metastases who experience seizures, as there is a risk of status epilepticus and death. Phenytoin is the most commonly used drug, but valproic acid and other anticonvulsants can also be used. Newer anticonvulsants have the advantage of fewer toxic side effects.[3][5]
  • Hyperosmolar agents (i.e., mannitol) can be given to reduce intracranial pressure.[5]
  • Recently, methylphenidate and donepezil have been used to improve cognition, mood, and quality of life.

Radiation Therapy

  • Control the growth of the tumor(s)
  • Control neurological symptoms, such as headaches or seizures
Indication Explanation

Multiple brain metastases

  • More than 3 metastatic brain tumors or in people with poor performance status

Single brain metastasis that cannot be removed by surgery

  • Brain tumors are in an inaccesible area or if the affected area would be damaged by surgery

Post surgical removal of a single brain metastasis

  • To destroy remnant cancer cells post surgery and reduce the chance of recurrence
  • One major concern with the use of whole brain radiotherapy is the risk of neurocognitive deficits, particularly short-term memory loss.[6]

Chemotherapy

  • Chemotherapy is the use of cytotoxic drugs that circulate throughout the body and destroy cancer cells.[7]
  • Chemotherapy may help shrink brain metastases and improve symptoms.
  • Due to the failure of most drugs to cross the intact blood–brain barrier (BBB), the role of chemotherapy in the treatment of intracerebral metastases has been viewed critically. Chemotherapy drugs are generally large (> 150 kDa), ionized, hydrophilic, and often protein-bound and therefore, ill-suited to penetrate the tight-junctions, electrochemical barrier, astrocyte foot-processes, and highly regulated transmembrane transport proteins of the central nervous system’s endothelial vasculature.
  • However, the effects of the blood-brain barrier may be over-estimated. First, there is evidence that the blood-brain barrier of intracerebral metastases is disrupted, as evidenced by the presence of peritumoral edema and the accumulation of contrast media during computed tomography or magnetic resonance assessments. Second, there is evidence of intracranial tumor response, even to drugs that in healthy systems have little central nervous system penetration.
  • The response rates of intracerebral metastases to platinum-based agents (cisplatin) in seven clinical trials of treatment-naive non-small cell lung cancer patients were similar to those achieved extra-cranially, ranging from 30 to 50%. However, the median survival time remained only 5–8 months in most cases. However, three trials using temozolomide achieved a response rate of only 0–10%, suggesting that the selection of chemotherapy drugs should be based mainly on their established anti-tumor activity to extracranial sites, and not on considerations of blood-brain barrier penetrance.
  • Responsiveness of brain metastases to chemotherapy depends on how sensitive the primary cancer is to chemotherapy drugs (chemosensitivity). For example, chemotherapy may be used to treat lung cancer, breast cancer, or melanoma that has spread to the brain.
  • The chemotherapy drugs used depend on the type of primary tumor. The drugs, dose, and schedule will vary for each individual.

Gallery


References

  1. 1.0 1.1 Andrew B. Lassman & Lisa M. DeAngelis (2003). "Brain metastases". Neurologic clinics. 21 (1): 1–23. PMID 12690643. Unknown parameter |month= ignored (help)
  2. 2.0 2.1 2.2 2.3 Khuntia, Deepak (2015). "Contemporary Review of the Management of Brain Metastasis with Radiation". Advances in Neuroscience. 2015: 1–13. doi:10.1155/2015/372856. ISSN 2356-6787.
  3. 3.0 3.1 3.2 Symptomatic treatment of brain metastasis. Wikipedia 2015. https://en.wikipedia.org/wiki/Brain_metastasis. Accessed on November 10, 2015
  4. 4.0 4.1 4.2 Radiation therapy for intracerebral metastases. Canadian cancer institute 2015. http://www.cancer.ca/en/cancer-information/cancer-type/metastatic-cancer/brain-metastases/treatment/?region=on. Accessed on November 13, 2015
  5. 5.0 5.1 5.2 Symptomatic treatment of brain metastases. Dr Bruno Di Muzio and Dr Trent Orton et al. Radiopaedia 2015. http://radiopaedia.org/articles/brain-metastases. Accessed on November 9, 2015
  6. Owen, Scott; Souhami, Luis (2014). "The Management of Brain Metastases in Non-Small Cell Lung Cancer". Frontiers in Oncology. 4. doi:10.3389/fonc.2014.00248. ISSN 2234-943X.
  7. Chemotherapy for intracerebral metastases. Canadian cancer institute 2015. http://www.cancer.ca/en/cancer-information/cancer-type/metastatic-cancer/brain-metastases/treatment/?region=on. Accessed on November 13, 2015


Template:WikiDoc Sources