Question

What management plan should be followed in patients with synchronous brain metastases?

Recommendation

Aggressive locoregional therapy may be considered in patients with a locally limited NSCLC and synchronous brain metastases that are eligible for neurosurgery or SRS.

Conclusions

Level 3
There are indications that aggressive locoregional therapy may be worthwhile in patients with a locally limited NSCLC and synchronous brain metastases that are treated with neurosurgery or SRS.
C: Flannery, 2008 (4);Yang, 2008 (5);Hu, 2006 (6)

Literature summary

Patients with a synchronous (compared to metachronous; within the course of the disease) presentation of brain metastases fall into two main groups. The largest group consists of patients who present with symptoms of brain metastases, after which the primary tumour is determined during screening. The second group consists of patients in whom asymptomatic brain metastases are determined at the initial staging of a primary tumour. Due to recent changes in the guidelines for staging of a number of common tumours which recommend screening for brain metastases, such as with stage III NSCLC (Silvestri, 2007 (1)), the second group has been increasing in the last few years. Please refer to related module asymptomatic brain metastases in this guideline for management of this last group of patients.

The percentage of patients presenting with brain metastases at the primary diagnosis varies highly with the type of primary tumour. In a monocentre database in the Netherlands consisting of 1202 patients who were treated for brain metastases, there was synchronous presentation (defined as an interval between the primary tumour and the brain metastases of less than 2 months) in 41% of patients with brain metastases of a lung carcinoma. This percentage was 25% for renal cell carcinoma, in contrast to only 3% for breast carcinoma and melanoma (Lagerwaard, 1999 (2)).

The treatment of brain metastases generally does not depend on the type of primary tumour, with the exception of tumours sensitive to chemotherapy such as germ cell tumours. While a detailed discussion of the locoregional treatment options in patients with synchronous brain metastases falls outside the scope of this guideline, it is worthwhile to mention a few comments with respect to the most common primary tumours for brain metastases: lung carcinoma, breast carcinoma and renal cell carcinoma.

Non-small cell lung carcinoma (NSCLC)
The results of a combined resection of a synchronous brain metastasis and an NSCLC have been described in multiple studies (Modi, 2009 (3)). These were mostly relatively small retrospective monocentre studies on patients with a solitary brain metastasis and a locally limited NSCLC without other extracranial metastases. A median survival of around two years and a 5-year survival of 11%-24% may be achieved with combined surgical treatment. This applies especially to patients without an indication of regional lymph node metastasis. Comparably favourable results have also been published more recently after SRS of synchronous brain metastases, combined with treatment ‘with curative intent' of the primary lung carcinoma (Flannery, 2008 (4);Yang, 2008 (5);Hu, 2006 (6)). Aggressive locoregional treatment may therefore be worthwhile in patients with a locoregionally limited lung carcinoma who have synchronous brain metastases that are eligible for neurosurgery or SRS. Regarding patients with extracranial metastases or patients who are not illegible for neurosurgery or SRS, there are no data available to support an aggressive locoregional treatment.

Breast carcinoma
Only 3-6% of the newly diagnosed patients with a breast carcinoma present with distant metastasis (Gnerlich, 2007 (7);Le Scodan, 2009 (8)). The proportion of patients with brain metastases at an initial diagnosis of stage IV breast carcinoma is very low, e.g. only 3% in the study by Le Scodan. The fraction of synchronous brain metastases is likewise limited in the series describing the treatment of brain metastases from breast carcinoma (Lagerwaard, 1999 (9)). All in all, a synchronous presentation of brain metastases and breast carcinoma is a rare clinical problem and as a result, there are no reliable data on the optimal treatment plan. Several recent publications show a possible added value of locoregional treatment in patients with an initial metastatic breast carcinoma (Cady, 2008 (10);Fields, 2007 (11)). However, these were mostly patients with bone metastases. In the only study in which brain metastases are specifically mentioned (Le Scodan, 2009 (8)), locoregional therapy (of the primary tumour) was only applied in 2 of the 18 patients with brain metastases. Locoregional therapy may, of course, be indicated if a threatening situation develops locally.

Renal cell carcinoma
Both symptomatic and asymptomatic synchronous brain metastases of renal cell carcinoma represent common problems. While the results of treatment with surgical resection and SRS are relatively favourable with a median survival duration of one to two years (Brown, 2008 (12);Scorsetti, 2009 (13)), there are barely any data on the value of locoregional treatment or nephrectomy. A prognostically favourable effect with chemotherapy or immunotherapy after SRS was observed in a retrospective series, but selection bias cannot be precluded here (Mori, 1998 (14)).

See here for the evidence table. 

References

  1. 1 - Silvestri GA, Gould MK, Margolis ML, Tanoue LT, McCrory D, Toloza E, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007 Sep;132(3 Suppl):178S-201S.
  2. 2 - Lagerwaard FJ, van der Hoorn EA, Verbakel WF, Haasbeek CJ, Slotman BJ, Senan S. Whole-brain radiotherapy with simultaneous integrated boost to multiple brain metastases using volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys 2009 Sep 1;75(1):253-9.
  3. 3 - Modi A, Vohra HA, Weeden DF. Does surgery for primary non-small cell lung cancer and cerebral metastasis have any impact on survival? Interact Cardiovasc Thorac Surg 2009 Apr;8(4):467-73.
  4. 4 - Flannery TW, Suntharalingam M, Regine WF, Chin LS, Krasna MJ, Shehata MK, et al. Long-term survival in patients with synchronous, solitary brain metastasis from non-small-cell lung cancer treated with radiosurgery. Int J Radiat Oncol Biol Phys 2008 Sep 1;72(1):19-23.
  5. 5 - Yang SY, Kim DG, Lee SH, Chung HT, Paek SH, Hyun KJ, et al. Pulmonary resection in patients with nonsmall-cell lung cancer treated with gamma-knife radiosurgery for synchronous brain metastases. Cancer 2008 Apr 15;112(8):1780-6.
  6. 6 - Hu C, Chang EL, Hassenbusch SJ, III, Allen PK, Woo SY, Mahajan A, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006 May 1;106(9):1998-2004.
  7. 7 - Gnerlich J, Jeffe DB, Deshpande AD, Beers C, Zander C, Margenthaler JA. Surgical removal of the primary tumor increases overall survival in patients with metastatic breast cancer: analysis of the 1988-2003 SEER data. Ann Surg Oncol 2007 Aug;14(8):2187-94.
  8. 8 - Le Scodan R, Stevens D, Brain E, Floiras JL, Cohen-Solal C, De La LB, et al. Breast cancer with synchronous metastases: survival impact of exclusive locoregional radiotherapy. J Clin Oncol 2009 Mar 20;27(9):1375-81.
  9. 9 - Lagerwaard FJ, Levendag PC, Nowak PJ, Eijkenboom WM, Hanssens PE, Schmitz PI. Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys 1999 Mar 1;43(4):795-803.
  10. 10 - Cady B, Nathan NR, Michaelson JS, Golshan M, Smith BL. Matched pair analyses of stage IV breast cancer with or without resection of primary breast site. Ann Surg Oncol 2008 Dec;15(12):3384-95.
  11. 11 - Fields RC, Jeffe DB, Trinkaus K, Zhang Q, Arthur C, Aft R, et al. Surgical resection of the primary tumor is associated with increased long-term survival in patients with stage IV breast cancer after controlling for site of metastasis. Ann Surg Oncol 2007 Dec;14(12):3345-51.
  12. 12 - Brown PD, Brown CA, Pollock BE, Gorman DA, Foote RL. Stereotactic radiosurgery for patients with "radioresistant" brain metastases. Neurosurgery 2008 Feb;62 Suppl 2:790-801.
  13. 13 - Scorsetti M, Facoetti A, Navarria P, Bignardi M, De SM, Ninone SA, et al. Hypofractionated stereotactic radiotherapy and radiosurgery for the treatment of patients with radioresistant brain metastases. Anticancer Res 2009 Oct;29(10):4259-63.
  14. 14 - Mori Y, Kondziolka D, Flickinger JC, Logan T, Lunsford LD. Stereotactic radiosurgery for brain metastasis from renal cell carcinoma. Cancer 1998 Jul 15;83(2):344-53.

Considerations

There is insufficient evidence for drawing a conclusion about the value of locoregional treatment of synchronous brain metastases from renal cell carcinoma or breast carcinoma. The same applies to patients with synchronous brain metastases from a locally advanced NSCLC.

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.