Brain metastases

Initiatief: NVN Aantal modules: 24

Brain metastases - Recurrence of brain metastases


What management plan should be followed with recurring brain metastases?


The decision whether and how recurrent brain metastases should be treated is to be made on an individual basis and depends on multiple factors, such as previous treatment, extracranial tumour activity, interval to recurrence and many other factors.
Patients in a good condition, with their extracranial tumour under control and who show a sustainable improvement (response of at least 6 months) by previous treatment of their brain metastasis, are eligible for treatment of recurrent brain metastasis. They have the following treatment possibilities:

  • SRS (1-3 lesions, lesions <3-4 cm)
  • Resection (solitary large recurrence, radionecrosis)
  • Chemotherapy (for multiple lesions of chemotherapy-sensitive primary tumours such as breast carcinoma, SCLC)
  • Targeted therapy (erlotinib or gefitinib for adenocarcinoma of the lung with EGFR mutation, non-smokers; lapatinib with chemotherapy for HER2/neu positive breast carcinoma patients)
  • Repeated WBRT

Note: Resection with WBRT should be considered in the case of a large symptomatic lesion together with multiple small lesions.

Maximum resection is recommended for a recurrence after SRS located within the SRS area. Alternatives here are again SRS, WBRT or chemotherapy.

In case of a recurrence after SRS outside of the earlier SRS area, another SRS is recommended. Alternatives are resection, WBRT or chemotherapy.

Another resection may be considered if there is a recurrence after resection. An alternative is SRS, and possibly chemotherapy/targeted therapy or WBRT.

Another WBRT is advised against for patients who develop a recurrence within 6 months after WBRT but who are in good condition and in whom the extracranial tumour activity is under control.

In the event of a recurrence as well as systemic tumour activity, systemic therapy may be considered (chemotherapy, targeted therapy).


In practice, focused anti-tumour treatment for recurring brain metastases is not generally provided, due to the fact that most patients showing symptoms of recurring brain metastases suffer from extracranial progressive disease and given these patients' poor general condition. For patients without progressive extracranial disease who are in a good condition and who had a good response to the first treatment of brain metastases, the usual treatment options (WBRT, SRS, surgery, possibly systemic therapy) may be considered; the same criteria apply here as for de novo brain metastases. The effect of repeated WBRT for a recurrence occurring within a period of 6 months is probably limited.

There are no studies that compare the different treatments for recurring brain metastases. As a result, no strict recommendation may be formulated regarding specific treatment for a patient with recurring brain metastases.


Level 3
There are indications that the RPA classification has the same prognostic value in recurrent brain metastases as for novo brain metastases.
C: Bindal, 1995 (16);Hoffman, 2001 (10) ;Noel 2001 (8);Sheehan, 2005 (29)

Level 3
There are indications that an interval of less than 4-6 months between the first treatment and the recurrence of brain metastases is prognostically unfavourable.
C: Bindal, 1995 (16);Sheehan, 2005 (29)

Level 3
There are indications that repeating WBRT is reasonably effective; 2 out of 3 patients experience neurological improvement or stabilisation.
C: Cooper, 1990 (1);Hazuka, 1988 (2);Kurup, 1980 (3);Sadikov, 2007 (4)

Level 3
There are indications that the effectiveness of SRS for recurring brain metastases after WBRT is equals that for de novo brain metastases.
C: Hoffman, 2001 (10)

Level 3
There are indications that chemotherapy is equally effective in patients with recurring brain metastases after WBRT as in patients with de novo brain metastases. The response rates are higher in chemotherapeutically naive patients, with effectiveness depending on the chemotherapeutic sensitivity of the primary tumour.
C: Boogerd, 1992 (21)

Level 3
There are indications that targeted therapy (lapatinib, erlotinib or gefitinib) after WBRT may bring about an objective response in brain metastases from NSCLC. Administering a combination of lapatinib and chemotherapy is more effective than administration of lapatinib only.
C: Ceresoli, 2004 (28);Lin, 2009 (26)

The most common treatment of brain metastases is WBRT. In combination with dexamethasone, an improvement in neurological symptoms may be achieved in approximately 75% of patients. The duration of the response is often limited: with an average survival among patients with brain metastases of 3-4 months, almost half of them will experience renewed increase in neurological complaints and deficits. These patients usually also suffer from extracranial progressive disease. The decision whether or not to treat a recurrent brain metastasis is therefore dependent on multiple factors, such as the nature of the neurological deficits, the condition of the patient, the severity of the extracranial tumour activity and associated treatment possibilities, previous treatment, the interval until the recurrence develops, localisation, size and number of recurrences and the chemotherapeutic sensitivity of the primary tumour. This decision therefore requires individual assessment. There are no comparative studies on the different treatments of recurring metastases. Studies on the benefit of different therapeutic options are retrospective and hence subject to selection bias.

Treatment options for recurring brain metastases are WBRT, SRS, neurosurgical resection, systemic therapy and symptomatic treatment only.

In the event of a recurrence of multiple brain metastases after prior WBRT, re-irradiation is occasionally performed; this is only considered when prior WBRT led to a response duration of at least 6 months. On the basis of retrospective studies in this patient group, a neurological response to repeated WBRT may be expected in approximately 1/3 of patients, a stabilisation in a further 1/3 (i.e. local control in 2 out of 3 patients), and further progression in the rest of the patients. Patients with recurring brain metastases of breast carcinoma appear to respond somewhat better than patients with NSCLC. Survival after re-irradiation in these selected patient groups is 2-4 months on average. The most common schedules for irradiation is 20 Gy or 25 Gy in 10 fractions. Reported toxicity in these patients with this short survival time is low (Cooper, 1990 (1);Hazuka, 1988 (2);Kurup, 1980 (3);Sadikov, 2007 (4)).

The same considerations and criteria apply to SRS as treatment of recurring brain metastases after prior WBRT as has been discussed previously for SRS. Local tumour control after SRS after prior WBRT does not appear different from SRS without prior irradiation, with local tumour control of ± 80% (Chao, 2008 (5);Flickinger, 1994 (6);Loeffler, 1990 (7);Noel, 2001 (8);Shaw, 2000 (9)). The duration of local tumour control after SRS is shorter for lesions with a diameter >2 cm (Chao, 2008 (5);Hoffman, 2001 (10)). Both SRS and WBRT may be considered in case new brain metastases develop outside the original SRS area (see above for criteria).

Regarding the treatment of a local recurrence within the earlier SRS area, considerations are more complex. Firstly, it is sometimes difficult to clearly differentiate between a tumour recurrence and tumour necrosis, although perfusion MRI scans may be helpful here (Hoefnagels, 2009 (11);Barajas, 2009 (12)). Histological verification by means of resection is appropriate in selected patients, while extirpation of both symptomatic tumour necrosis and tumour recurrence may lead to a better neurological recovery.

If there is no indication or possibility to perform a resection, and the chances of recurring tumour growth are high, a second local SRS treatment may be considered. Although experience in this is limited, local tumour control for an average duration of approximately 5 months or longer has been described (Kwon, 2007 (13);Yamanaka, 1999 (14)). The risk of radionecrosis after 2 session of SRS is approximately 20% (Kwon, 2007 (13)).

There is an indication for neurosurgical intervention if local recurrence occurs within the SRS area (e.g. in case of a large tumour volume; see SRS / neurosurgical resection with or without WBRT). Repeated surgery of recurring brain metastases has been described in multiple retrospective studies, mostly in patients with NSCLC. In patients with favourable prognostic factors (a relatively young age, a good general condition, controlled extracranial tumour activity, an interval since 1st treatment of at least 5 months), repeated surgery leads to an average local tumour control of 6 months, and a median survival of 6-12 months (Arbit 1995 (15);Bindal, 1995 (16);Boogerd, 1997 (17);Schackert, 2001 (18)). The risk of complications is relatively low and no different than during the first resection (Arbit, 1995 (15)).

Systemic therapy
The benefit of chemotherapy for recurring brain metastases has barely been systematically studied. In a prospective multicentre study in which 115 patients with recurring brain metastases from the most frequent primary tumours were treated with a schedule consisting of multiple alkylating cytostatics, uncommon for the Netherlands, a response was found in approximately a quarter of patients with a breast carcinoma, SCLC or NSCLC, and stabilisation in approximately half of the patients with a median response duration of approximately 3 months (Kaba, 1997 (19)). A similar response was reported after carboplatin for recurring brain metastases of a SCLC (Groen, 1993 (20)). In patients with a breast carcinoma, the chance of recurring brain metastases responding to standard chemotherapy of after WBRT is probably not different from the response of de novo brain metastases, and may be >50% depending on the chemotherapy already administered (Boogerd, 1992 (21);Ekenel, 2007 (22)). Single agent temozolomide is barely effective as treatment of recurring brain metastases with a reported response of <10%, mainly with NSCLC (Abrey, 2001 (23)). It does not appear to be of added value in combination with other cytostatics (Iwamoto, 2008 (24);Rivera, 2006 (25)).

Targeted therapy
In a large phase 2 study of HER2/neu positive breast carcinoma patients with recurring brain metastases after previous WBRT, lapatinib was the only treatment that resulted in an objective response (>50% tumour reduction) of 6% and a less pronounced response (>20% tumour reduction) of 21%. In combination with capecitabine, these response percentages were 20% and 40%, respectively (Lin, 2009 (26)). The tyrosine kinase inhibitors gefitinib and erlotinib are mainly effective for adenocarcinoma of the lung with specific mutations in the EGFR gene. For erlotinib, long-term response of recurring brain metastases from NSCLC after WBRT has been documented (Von Pawel, 2008 (27)). Gefitinib for recurring brain metastases from adenocarcinoma of the lung after WBRT resulted in local tumour control of approximately 50% (Ceresoli, 2004 (28)); the EGFR mutation status was not determined in this study.

Click here for the evidence table.

  1. 1 - Cooper JS, Steinfeld AD, Lerch IA. Cerebral metastases: value of reirradiation in selected patients. Radiology 1990 Mar;174(3 Pt 1):883-5.
  2. 2 - Hazuka MB, Kinzie JJ. Brain metastases: results and effects of re-irradiation. Int J Radiat Oncol Biol Phys 1988 Aug;15(2):433-7.
  3. 3 - Kurup P, Reddy S, Hendrickson FR. Results of re-irradiation for cerebral metastases. Cancer 1980 Dec 15;46(12):2587-9.
  4. 4 - Sadikov E, Bezjak A, Yi QL, Wells W, Dawson L, Millar BA, et al. Value of whole brain re-irradiation for brain metastases--single centre experience. Clin Oncol (R Coll Radiol ) 2007 Sep;19(7):532-8.
  5. 5 - Chao ST, Barnett GH, Vogelbaum MA, Angelov L, Weil RJ, Neyman G, et al. Salvage stereotactic radiosurgery effectively treats recurrences from whole-brain radiation therapy. Cancer 2008 Oct 15;113(8):2198-204.
  6. 6 - Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, Goodman ML, Shaw EG, et al. A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994 Mar 1;28(4):797-802.
  7. 7 - Loeffler JS, Kooy HM, Wen PY, Fine HA, Cheng CW, Mannarino EG, et al. The treatment of recurrent brain metastases with stereotactic radiosurgery. J Clin Oncol 1990 Apr;8(4):576-82.
  8. 8 - Noel G, Proudhom MA, Valery CA, Cornu P, Boisserie G, Hasboun D, et al. Radiosurgery for re-irradiation of brain metastasis: results in 54 patients. Radiother Oncol 2001 Jul;60(1):61-7.
  9. 9 - Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 2000 May 1;47(2):291-8.
  10. 10 - Hoffman R, Sneed PK, McDermott MW, Chang S, Lamborn KR, Park E, et al. Radiosurgery for brain metastases from primary lung carcinoma. Cancer J 2001 Mar;7(2):121-31.
  11. 11 - Hoefnagels FW, Lagerwaard FJ, Sanchez E, Haasbeek CJ, Knol DL, Slotman BJ, et al. Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence. J Neurol 2009 Jun;256(6):878-87.
  12. 12 - Barajas RF, Chang JS, Sneed PK, Segal MR, McDermott MW, Cha S. Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AJNR Am J Neuroradiol 2009 Feb;30(2):367-72.
  13. 13 - Kwon KY, Kong DS, Lee JI, Nam DH, Park K, Kim JH. Outcome of repeated radiosurgery for recurrent metastatic brain tumors. Clin Neurol Neurosurg 2007 Feb;109(2):132-7.
  14. 14 - Yamanaka K, Iwai Y, Yasui T, Nakajima H, Komiyama M, Nishikawa M, et al. Gamma Knife radiosurgery for metastatic brain tumor: the usefulness of repeated Gamma Knife radiosurgery for recurrent cases. Stereotact Funct Neurosurg 1999;72 Suppl 1:73-80.
  15. 15 - Arbit E, Wronski M, Burt M, Galicich JH. The treatment of patients with recurrent brain metastases. A retrospective analysis of 109 patients with nonsmall cell lung cancer. Cancer 1995 Sep 1;76(5):765-73.
  16. 16 - Bindal RK, Sawaya R, Leavens ME, Hess KR, Taylor SH. Reoperation for recurrent metastatic brain tumors. J Neurosurg 1995 Oct;83(4):600-4.
  17. 17 - Boogerd W, Hart AA, Tjahja IS. Treatment and outcome of brain metastasis as first site of distant metastasis from breast cancer. J Neurooncol 1997 Nov;35(2):161-7.
  18. 18 - Schackert G, Steinmetz A, Meier U, Sobottka SB. Surgical management of single and multiple brain metastases: results of a retrospective study. Onkologie 2001 Jun;24(3):246-55.
  19. 19 - Kaba SE, Kyritsis AP, Hess K, Yung WK, Mercier R, Dakhil S, et al. TPDC-FuHu chemotherapy for the treatment of recurrent metastatic brain tumors. J Clin Oncol 1997 Mar;15(3):1063-70.
  20. 20 - Groen HJ, Smit EF, Haaxma-Reiche H, Postmus PE. Carboplatin as second line treatment for recurrent or progressive brain metastases from small cell lung cancer. Eur J Cancer 1993;29A(12):1696-9.
  21. 21 - Boogerd W, Dalesio O, Bais EM, van der Sande JJ. Response of brain metastases from breast cancer to systemic chemotherapy. Cancer 1992 Feb 15;69(4):972-80.
  22. 22 - Ekenel M, Hormigo AM, Peak S, DeAngelis LM, Abrey LE. Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 2007 Nov;85(2):223-7.
  23. 23 - Abrey LE, Olson JD, Raizer JJ, Mack M, Rodavitch A, Boutros DY, et al. A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 2001 Jul;53(3):259-65.
  24. 24 - Iwamoto FM, Omuro AM, Raizer JJ, Nolan CP, Hormigo A, Lassman AB, et al. A phase II trial of vinorelbine and intensive temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 2008 Mar;87(1):85-90.
  25. 25 - Rivera E, Meyers C, Groves M, Valero V, Francis D, Arun B, et al. Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 2006 Sep 15;107(6):1348-54.
  26. 26 - Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 2009 Feb 15;15(4):1452-9.
  27. 27 - von Pawel J, Wagner H, Duell T, Poellinger B. Erlotinib in patients with previously irradiated, recurrent brain metastases from non-small cell lung cancer: two case reports. Onkologie 2008 Mar;31(3):123-6.
  28. 28 - Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crino L, Villa E. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 2004 Jul;15(7):1042-7.
  29. 29 - Sheehan J, Kondziolka D, Flickinger J, Lunsford LD. Radiosurgery for patients with recurrent small cell lung carcinoma metastatic to the brain: outcomes and prognostic factors. J Neurosurg 2005 Jan;102 Suppl:247-54.

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

  • 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


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.


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


Samenstelling werkgroep



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.





Dr. L.V. Beerepoot




consultatie / advisering




Dr. W. Boogerd




Dr. M. van Dijk

Schering Plough



Dr. A.C. Dingemans




Astra Zeneca



consultatie / advisering / wetenschappelijk onderzoek

consultatie / advisering

consultatie / advisering / wetenschappelijk onderzoek

consultatie / advisering / wetenschappelijk onderzoek




Dr. C.A. van Es




Dr. A. de Graeff




consultatie / advisering

consultatie / advisering


Dr. P.A.M. Hofman

Strijker NL B.V.

Medtronics Spinal

Bayer Health Care

Johnson & Johnson






Dr. H.F.M. van der Heijden

Astra Zeneca

Sanofi Aventis




consultatie / advisering

consultatie / advisering

consultatie / advisering / wetenschappelijk onderzoek







Dr. R.L.H. Jansen



Sanofi Aventis

Diverse firma's



wetenschappelijk onderzoek





Dr. F.J. Lagerwaard

Roche Nederland

Roche NL-longadviesraad

Brain Lab

Varian Medical Systems

wetenschappelijk onderzoek

consultatie / advisering







Method of development

evidence based


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 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.