Question

See discription and conclusions of the pathogenesis and pathofysiology:

Conclusions

In 75% of cases, brain metastases are derived from three types of tumours: lung carcinoma (SCLC and NSCLC), breast carcinoma and melanoma. The majority of patients with brain metastases present with manifest metastases in other sites as well.
Nussbaum, 1996 (8);Gavrilovic and Posner, 2005 (5)

Literature summary

The clinical finding that different tumour types exhibit preferred localisations for metastasis forms the basis for the seed-and-soil-hypothesis, which postulates that specific characteristics of tumour cells lead to a specific affinity for particular organs (Posner, 1995 (1);Hart, 1992 (2)). The genetic changes specifically underlying metastasis to the brain are the topic of a recent extensive study (Bos, 2009 (3);Nguyen, 2009 (4)). Nevertheless, the molecular basis for metastasis to the brain remains largely unknown. Haematogenous metastasis appears the most common mechanism (Gavrilovic and Posner, 2005 (5)). Primary tumours often metastasise to the lungs because tumour cells enter the pulmonary capillary system from the venous circulation via the heart. Primary lung carcinomas and lung metastases easily spread to the brain since 20% of the cardiac output runs through here. Macroscopic lung metastases or a primary lung carcinoma are indeed found in 70% of patients with brain metastases (Posner, 1995 (1)).
Brain metastases preferably occur in the watershed area (borders between the vascular supply) of the large cerebral blood vessels and in the capillaries and venules at the transition from white to grey matter. Tumour cells or tumour embolisms get stuck in the circulation and adhere to organ-specific receptors on the endothelium and basal membrane, after which they invade the parenchyma. Distribution to the supra- or infratentorial part of the brain is related to the blood supply; 80% of brain metastases are localised in the cerebrum. Focal symptoms are caused by displacement of and pressure on brain tissue by the metastasis and surrounding vasogenic oedema. Oedema develops as a result of a deficient blood-brain barrier (BBB) in newly formed tumours vessels or through a disruption of the BBB in normal surrounding brain tissue. Plasma fluid leaks to the interstitium in the white matter and follows the white matter pathways in a finger-shaped pattern. It is unclear whether oedema is itself toxic to the brain or that symptoms are caused by the mass effect (Posner, 1995 (1)). Destruction of brain tissue is less common given the mainly expansive growth of brain metastases; effective treatment of usually leads to substantial improvement or recovery of neurological complaints, although metastases may microscopically invade brain tissue, especially those from melanoma and renal cell carcinoma. Irritation of the cortex by the tumour and/or oedema causes epileptic seizures. This is relatively common with melanoma metastases. Generalised symptoms are the result of increased intracranial pressure due to tumour mass and surrounding oedema. Hydrocephalus and compression of venous vessels or sinuses may also cause an elevation in intracranial pressure with associated signs (Posner, 1995 (1)).

An intact BBB represents a refuge for microscopic brain metastases that may lie dormant behind the BBB for years. The introduction of effective systemic therapy leads to an increased incidence of brain metastases as a first location of recurrence, since chemotherapy is unable to pass the intact BBB (Lin, 2007 (6);Gavrilovic and Posner, 2005 (5)). When brain metastases enhance, the BBB is disrupted, which does not necessarily entail that any chemotherapeutic agent can easily pass the disrupted BBB. Passage depends (amongst other things) on the electrical charge and lipophilicity of the chemotherapeutic agent, its binding to plasma proteins, the size of the molecule and the functioning of membrane pump proteins (Gerstner and Fine, 2007 (7)).

References

  1. 1 - Posner JB. Intracranial metastases. In: Posner JB, editor. Neurologic complications of cancer.Philadelphia: FA Davis; 1995. p. 77-110.
  2. 2 - Hart IR, Saini A. Biology of tumour metastasis. Lancet 1992 Jun 13;339(8807):1453-7.
  3. 3 - Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, et al. Genes that mediate breast cancer metastasis to the brain. Nature 2009 Jun 18;459(7249):1005-9.
  4. 4 - Nguyen DX, Chiang AC, Zhang XH, Kim JY, Kris MG, Ladanyi M, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 2009 Jul 10;138(1):51-62.
  5. 5 - Gavrilovic IT, Posner JB. Brain metastases: epidemiology and pathophysiology. J Neurooncol 2005 Oct;75(1):5-14.
  6. 6 - Lin NU, Winer EP. Brain metastases: the HER2 paradigm. Clin Cancer Res 2007 Mar 15;13(6):1648-55.
  7. 7 - Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 2007 Jun 1;25(16):2306-12.
  8. 8 - Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 1996 Oct 15;78(8):1781-8.

Authorization date and validity

Last review : 01-07-2011

Last authorization : 01-07-2011

The period of validity of the guideline (maximum of 5 years) is being monitored by IKNL. For various reasons, it may be necessary to revise the guideline earlier than intended. Sections of the guideline will be amended in the interim, when required.

Initiative and authorization

Initiative : Nederlandse Vereniging voor Neurologie

Authorized by:
  • Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
  • Nederlandse Vereniging voor Medische Oncologie
  • Nederlandse Vereniging voor Neurochirurgie
  • Nederlandse Vereniging voor Neurologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie
  • Verpleegkundigen en Verzorgenden Nederland
  • Nederlandse Vereniging voor Psychosociale Oncologie
  • Nederlands Instituut van Psychologen

Scope and target group

Objective

The guideline covers the processes of diagnosis, treatment, information provision and guidance of adult patients with metastases in the brain originating from solid tumours, thereby focusing on topical clinical problems encountered in daily practice. The guideline's recommendations aim to aid practitioners in their decision-making support when facing these problems. The recommendations are based on the highest available grade of scientific evidence and on consensus within the guideline development group. The guideline provides information on how the recommendations have been reached from the evidence.

 

The guideline may be used to provide information to patients and offers points of reference for transmural agreements or local protocols to facilitate implementation.

Users

The guideline is intended for all professionals involved in the diagnostics, treatment and guidance of adult patients with brain metastases of solid tumours. These professionals include:

  • Primary specialists: neurologists, neurosurgeons, radiotherapists, medical oncologists, pulmonologists, (oncology) nurses, general practitioners, specialists (working) in palliative care
  • Supporting specialists: radiologists, pathologists
  • Healthcare providers specialised in psychosocial care: social workers, psychologists, psychiatrists and geriatric medicine specialists

 

Members of the guideline panel

2011:

Chair:

mw. dr. J.M.M. Gijtenbeek, neuroloog, Universitair Medisch Centrum St Radboud, Nijmegen

Other members:

dr. L.V. Beerepoot, medisch oncoloog, St. Elisabeth Ziekenhuis, Tilburg

dr. W. Boogerd, neuroloog, Nederlands Kanker Instituut / Antoni van Leeuwenhoekziekenhuis, Slotervaartziekenhuis, Amsterdam

mw. S. Bossmann, nurse practitioner, Universitair Medisch Centrum St Radboud Nijmegen

mw. dr. M. van Dijk, internist-oncoloog, Maastricht Universitair Medisch Centrum, Maastricht

mw. dr. A.C. Dingemans, longarts, Maastricht Universitair Medisch Centrum, Maastricht

mw. dr. C. van Es, radiotherapeut-oncoloog, Utrecht Universitair Medisch Centrum, Utrecht, niet actief betrokken (is betrokken geweest bij het initiëren van de werkgroep maar kon vanwege onvoorziene omstandigheden niet aan de totstandkoming van de richtlijn meewerken)

dr. A. de Graeff, medisch oncoloog, Utrecht Universitair Medisch Centrum, Utrecht

dr. P.E.J. Hanssens, radiotherapeut-oncoloog, Gamma Knife Centrum, Tilburg

dr. H.F.M. van der Heijden, longarts, Universitair Medisch Centrum St Radboud, Nijmegen

dr. M.A.A.M. Heesters, radiotherapeut-oncoloog Universitair Medisch Centrum Groningen, Groningen

dr. P.A. M. Hofman, neuroradioloog, Maastricht Universitair Medisch Centrum, Maastricht

dr. R.L.H. Jansen, medisch oncoloog, Maastricht Universitair Medisch Centrum, Maastricht, niet actief betrokken

drs. E. Kurt, neurochirurg, Medisch Centrum Alkmaar

dr. F. J. Lagerwaard, radiotherapeut-oncoloog, Vrije Universiteit Medisch Centrum, Amsterdam

mw. prof.dr. J.B. Prins, klinisch psycholoog, Universitair Medisch Centrum St Radboud, Nijmegen

drs. J.H.C. Voormolen, neurochirurg, Leids Universitair Medisch Centrum, Leiden

drs. V.K.Y. Ho, epidemioloog/procesbegeleider, Integraal Kankercentrum Nederland (IKNL), locatie Utrecht

mw. M.L. van de Kar, ambtelijk secretaris, Landelijke Werkgroep Neuro-Oncologie (LWNO), Bussum

Ondersteuning methodologie

mw. dr. M. Brink, epidemioloog, IKNL, locatie Utrecht

drs. J.M. van der Zwan, MSc, epidemiologisch onderzoeker, IKNL, locatie Enschede

 

Leden werkgroep voorgaande revisie (2004)

dr. R.H. Boerman, neuroloog, Rijnstate Ziekenhuis, Arnhem (voorzitter)

dr. W. Boogerd, neuroloog, Nederlands Kanker Instituut / Antoni van Leeuwenhoekziekenhuis, Slotervaartziekenhuis, Amsterdam

mw. dr. W.M.H. Eijkenboom, radiotherapeut-oncoloog, Daniel den Hoed Kliniek, Rotterdam

dr. P.E.J. Hanssens, radiotherapeut-oncoloog, Dr. Bernard Verbeeten Instituut, Tilburg

dr. R.L.H. Jansen, medisch oncoloog, Academisch Ziekenhuis Maastricht

dr. F. J. Lagerwaard, radiotherapeut-oncoloog, Vrije Universiteit Medisch Centrum, Amsterdam

prof.dr. C.J.A. Punt, inetrnist-oncoloog, Academisch Ziekenhuis Nijmegen

drs. J.H.C. Voormolen, neurochirurg, Leids Universitair Medisch Centrum, Leiden

prof.dr. J.T. Wilmink, neuroradioloog, Academisch Ziekenhuis Maastricht

dr. J.G. Wolbers, neurochirurg, Academisch Ziekenhuis Dijkzigt, Rotterdam

 

 

Declaration of interest

All guideline working group members were asked to fill in a conflict of interest declaration, in which they stated ties with the medical industry at the start and completing the guideline process. An overview of these conflict of interest declarations can be found below. The remaining guideline working group members have declared that at this moment or in the last three years they have not performed any activities on invitation or with subsidy/sponsoring by the medical industry.
   

Lid

Firma

Activiteit

Overig

Dr. L.V. Beerepoot

Pfizer

Merck

Cephalon

consultatie / advisering

congres

congres

congres

Dr. W. Boogerd

Mundipharma

 

congres

Dr. M. van Dijk

Schering Plough

 

congres

Dr. A.C. Dingemans

Roche

 

Lilly

Astra Zeneca

 

Glaxo

consultatie / advisering / wetenschappelijk onderzoek

consultatie / advisering

consultatie / advisering / wetenschappelijk onderzoek

consultatie / advisering / wetenschappelijk onderzoek

congres

 

cursus

Dr. C.A. van Es

Elektra

 

congres

Dr. A. de Graeff

 

Nycomed

Wyeth

consultatie / advisering

consultatie / advisering

 

Dr. P.A.M. Hofman

Strijker NL B.V.

Medtronics Spinal

Bayer Health Care

Johnson & Johnson

 

congres

congres

congres

congres

Dr. H.F.M. van der Heijden

Astra Zeneca

Sanofi Aventis

Lilly

 

Roche

consultatie / advisering

consultatie / advisering

consultatie / advisering / wetenschappelijk onderzoek

 

congres

congres

congres

 

congres

Dr. R.L.H. Jansen

Pfizer

Roche

Sanofi Aventis

Diverse firma's

 

 

wetenschappelijk onderzoek

studies

congres

congres

congres

Dr. F.J. Lagerwaard

Roche Nederland

Roche NL-longadviesraad

Brain Lab

Varian Medical Systems

wetenschappelijk onderzoek

consultatie / advisering

 

 

 

congres

congres

   

Method of development

Evidence based

Implementation

Considerations concerning the implementation of the guideline as well as the feasibility of recommendations have been taken into account as much as possible in drafting the revised guideline.

 

The guideline is summarised and may be consulted in its entirety on http://www.oncoline.nl/. The guideline has been brought to the attention of members of the LWNO, hospitals in the Netherlands, oncology commissions, as well as the scientific and professional associations involved. To further stimulate awareness and implementation of the guideline, regional tumour working groups on neuro-oncology of IKNL were invited to discuss its recommendations.

 

Given the highly progressive and unfavourable course of the disease, the guideline development group decided not to develop care indicators to measure the level of guideline implementation.