Question

What is the role of systemic therapy of symptomatic brain metastases (chemotherapy, hormonal therapy, tyrosine kinase inhibitors and other (new) drugs)?

• what are the indications?

• which interactions are possible for radiotherapy and radiosurgery?

• what are the cerebral side effects?

 

Recommendation

Non-small cell lung carcinoma (NSCLC)
Systemic therapy is generally not the treatment modality of choice for symptomatic brain metastases from NSCLC.

If chemotherapy is applied to treat symptomatic brain metastases from NSCLC, provision of radiotherapy may be delayed and only administered if there is no response to chemotherapy.

Small cell lung carcinoma (SCLC)
Patients with SCLC who present with symptomatic brain metastases are preferably treated with systemic chemotherapy and WBRT.

Breast carcinoma
The treatment of choice with brain metastases from breast carcinoma is local (radiotherapy and/or surgery).

If systemic treatment is applied, however, the choice of specific schedules of systemic therapy should depend on previously administered systemic treatment and on tumour characteristics and not on the presence of brain metastases.

After local treatment of brain metastases in patients with HER2/neu positive breast carcinoma, treatment with trastuzumab (possibly in combination with chemotherapy) may be continued upon systemic response.

Melanoma
Systemic therapy as primary treatment modality in patients with symptomatic brain metastases from melanoma is advised against.

Germ cell tumours
The treatment of patients with brain metastases from germ cell tumours should be performed in a specialised centre. Primary resection is generally indicated in patients with large, symptomatic brain metastases. Other patients are usually treated with standard platinum-containing chemotherapy. Local treatment may subsequently still be performed (surgery, SRS or WBRT) in case of incomplete remission.

Given the good chance of curation in this group of patients, the possible long-term neurocognitive damage must be taken into account when determining the fractionation of the radiotherapy.

Other tumour types
The guideline development group is of the opinion that the decision whether or not to use systemic therapy for treating brain metastases from other tumours than those outlined above should be made on an individual basis.

Combination therapy
Concurrent treatment with systemic therapy (chemotherapy or other radiosensitisers) and radiotherapy for brain metastases is not recommended.

Conclusions

Non-small cell lung carcinoma (NSCLC)
Level 2
It is plausible that, for patients receiving systemic treatment for brain metastases from NSCLC who have not been treated previously with chemotherapy, the intracranial response (27-28%), is comparable to the extracranial response.
A2: Robinet, 2001 (3)
B: Lee, 2008 (2)

Level 2
It is plausible that the timing of WBRT in patients with brain metastases from NSCLC, when systemic chemotherapy is also provided, does not influence the progression-free or total survival.
A2: Robinet, 2001 (3)
B: Lee, 2008 (2)

Small cell lung carcinoma (SCLC)
Level 3
There are indications that simultaneous treatment of patients with chemotherapy and radiotherapy (WBRT) leads to a better response and a longer time to progression of the brain metastases than chemotherapy with delayed radiotherapy. No extra neurological toxicity was observed.
A2: Postmus, 2000 (11)

Breast carcinoma
Level 3
There are indications that systemic chemotherapy in breast carcinoma patients with brain metastases may lead to an intracranial response of 30-60%.
C: Boogerd, 1992 (12);Colleoni, 1997 (13);Franciosi, 1999 (14)

Level 4
There are indications that, after local treatment of brain metastases, patients with HER2/neu positive breast carcinoma may have a prolonged and progression-free survival if treatment with trastuzumab (and chemotherapy) is continued.
D: Opinion of the development group, supported by literature (Church, 2008 (17);Bartsch, 2007 (18))

Melanoma
Level 3
There are indications that temozolomide as monotherapy leads to intracranial response percentages of 7%-9% in patients with brain metastases from a melanoma.
B: Boogerd, 2007 (21)
C: Agarwala, 2004 (20)

Germ cell tumours
Level 3
There are indications that, in patients with brain metastases derived from germ cell tumours, complete remission can be achieved with chemotherapy, possibly combined with surgery and/or radiotherapy.
C: Gremmer, 2008 (24);Gerl, 1996 (25);Evans, 1995 (35)

Combination therapy
Level 2
It is plausible that the addition of temozolomide to radiotherapy in patients with brain metastases does not lead to a longer survival.
B: Antonadou, 2002 (27);Verger, 2005 (28)

Level 2
It is plausible that the application of radiosensitisers combined with radiotherapy in patients with brain metastases does not lead to a longer survival or better intracranial response.
A2: Mehta, 2009 (34)
B: Suh, 2006 (33)

Literature summary

Systemic or medication-based therapy has a modest role in the treatment of patients with symptomatic brain metastases. The decision to treat patients depends, amongst other things, on the extensiveness of the extra- and intracranial disease, the KPS and neurological symptoms (see Whether or not treatment should be performed). The literature generally considers patients with non-resectable brain metastases.

The blood-brain barrier (BBB) has long been considered a limiting factor for therapeutic intracerebral concentrations of especially large and lipophobic medication. However, the BBB is regularly disturbed in the presence of brain metastases, as has been demonstrated by staining after contrast during imaging. Brain metastases therefore appear to respond in the same way to systemic therapy as metastases elsewhere in the body.

Medications that disturb the BBB such as mannitol appear to have a biological effect but have been insufficiently studied to be applied outside a trial context (Fortin, 2007 (1)).

No research has been conducted to evaluate whether corticosteroids given during systemic therapy strengthen the BBB, thereby preventing medication from reaching the metastases.

The choice of systemic treatment is directed by several factors:

  • the primary tumour and the associated corresponding sensitivity of the metastases to systemic therapy
  • the presence and growth of extracranial disease
  • (in)accessibility for surgery and radiotherapy
  • earlier treatment of the metastases

Since the choice of therapy depends on the characteristics of the primary tumour, the various treatment options are discussed per tumour type.

Non-small cell lung carcinoma (NSCLC)

In a small study, 48 not previously treated patients with synchronous brain metastases from NSCLC who were asymptomatic after dexamethasone, were randomised between primary treatment with chemotherapy (gemcitabine and vinorelbine in a 3-weekly schedule) followed by WBRT versus WBRT followed by chemotherapy (Lee, 2008 (2)). The study stratified for performance status and number of brain metastases (> or <3). There was no statistically significant difference in intracranial response between both groups (28% for chemotherapy first and 39% for WBRT first), although 4 of the 21 patients in the group receiving WBRT first were not given follow-up treatment with chemotherapy because of clinical decline or death. There was no difference in progression-free survival (3.6 versus 4.4 months, chemotherapy first versus WBRT first) or in survival (median survival 9.1 versus 9.9 months). Neurological functioning worsened in both groups. The intracranial response had a strong correlation with the extracranial response.

In another different prospective study of 171 patients (Robinet, 2001 (3)), patients with symptomatic brain metastases from NSCLC who had not been treated before were randomised between synchronous treatment with chemotherapy (cisplatin/vinorelbine)+WBRT and chemotherapy followed by WBRT in the case of non-response after 2, 4 or 6 courses of chemotherapy. Eventually, 57/86 (66%) of the patients in the delayed WBRT group were irradiated. No difference was found in intracranial response (33% and 27% respectively) and extracranial response (20% and 21% respectively), median survival (21 and 24 weeks) and treatment-related toxicity.

No data are available on the treatment of symptomatic brain metastases with systemic therapy without the addition of WBRT as mentioned in the treatment protocol.

Other studies on patients with brain metastases from NSCLC treated with chemotherapy involved metastases that were asymptomatic (see Asymptomatic brain metastases).
Patients who present with limited intracranial and extracranial disease may undergo aggressive treatment with curative intent as outlined in Synchronous brain metastases.

Small cell lung carcinoma (SCLC)
Patients who initially present with brain metastases have an extensive disease (stage IV) SCLC. Systemic chemotherapy is often commenced as first-line treatment. Some smaller studies report intracranial response percentages of 27% in asymptomatic patients (Seute, 2006 (4)) to 79% in those with symptomatic brain metastases (Kantarjian, 1984 (5);Lee, 1989 (6);Humblet, 1989 (7);Twelves, 1990 (8);Kristjansen, 1993 (9);Tummarello, 1998 (10)). However, these studies were non-controlled and therefore highly sensitive to selection bias, and it is therefore unlikely that the abovementioned percentages are achievable in daily practice.

In a prospective randomised study of 120 patients presenting with brain metastases from SCLC who had been previously treated for SCLC (and who have therefore previously received chemotherapy, i.e. in 72% of cases) (Postmus, 2000 (11)), randomisation took place between direct WBRT and chemotherapy (teniposide) versus delayed WBRT after initial treatment with chemotherapy. Direct WBRT after chemotherapy resulted in a better intracranial response (57 vs 22%) and prolonged time to progression. There was no significant difference in extracranial response (33 vs 20 %) and also no significant difference in survival (median survival was approximately 3 months in both groups).

See the guideline on SCLC for systemic treatment (link) and for the indications for PCI (link).

Breast carcinoma
Small studies in which patients with brain metastases from breast carcinoma were primarily treated with systemic therapy reported an intracranial chance of response of 30-60% (Boogerd, 1992 (12);Colleoni, 1997 (13);Franciosi, 1999 (14)); however, the chemotherapy schedules used in these studies have become obsolete. Although no comparative studies are available, intracranial response percentages appear comparable with to those of extracranial metastases. There is insufficient literature to formulate recommendations regarding the choice of specific chemotherapeutic agents that easily pass the BBB. In practice, the choice for systemic therapy is primarily based on the patient's specific situation and on earlier treatment regimes.

There are no comparative studies available that compare systemic therapy with other treatment modalities in patients with brain metastases from breast carcinoma.

There is a modest role for lapatinib in patients with brain metastases from HER2/neu positive breast carcinoma that are progressive after earlier radiotherapy (Lin, 2008_JCO (15)). The chance of response improves somewhat when capecitabine is added to lapatinib (20% intracranial response in a selected population) (Lin, 2009 (16)). See also Recurrence of brain metastases.

Multiple studies have demonstrated an increase in overall survival and probably also progression-free survival among patients with brain metastases from HER2/neu positive breast carcinoma if treatment with trastuzumab (and chemotherapy) is continued after local treatment (Church, 2008 (17);Bartsch, 2007 (18)).

Melanoma
Brain metastases are relatively common in patients with melanoma (21% reported in patients with stage IV melanoma) (Fogarty, 2006 (19)).
Treatment with temozolomide was evaluated in a phase-2 study. An intracranial response percentage of 7% has been reported in patients with brain metastases who did not require direct radiotherapy and who were not pretreated (Agarwala, 2004 (20)). In a retrospective analysis of patients with a melanoma who were treated with temozolomide within a trial context, patients with small (<2 cm) brain metastases were identified (Boogerd, 2007 (21)), and an objective intracranial response of 9% was reported for this group.

Germ cell tumours
Both standard and rescue chemotherapy may be curative for the treatment of germ cell tumours that have metastasised to the brain. In a German series comprising 132 patients with metastatic germ cell tumours that were treated within a trial context with high dose chemotherapy, either in or not in combination with radiotherapy and surgery, 22 patients were found to have brain metastases (of which 32% were symptomatic). Eight of the 22 patients achieved CR (follow-up 4-20 years), 7 of the 8 patients also underwent a craniotomy and WBRT. The reported 2-year disease-free survival of 77% in patients with brain metastases is comparable to the disease-free survival of the series' patients who do not have brain metastases (Kollmannsberger, 2000 (22)). These results were confirmed in other series (Bokemeyer, 1997 (23);Gremmer, 2008 (24)).

The treatment of brain metastases consists of standard platinum-containing chemotherapy, preceded with resection in the case of large and/or haemorrhagic brain metastases. In the case of incomplete intracranial remission after chemotherapy, additional local therapy is administered (WBRT and/or SRS and/or neurosurgical resection) (Bokemeyer, 1997 (23);Gerl, 1996 (25);Gremmer, 2008 (24);Kollmannsberger, 2000 (22);Nonomura, 2009 (26)).

The treatment is curative in nature and the possible long-term neurocognitive damage caused by irradiation must therefore be taken into account in deciding over the appropriate radiotherapy schedule.

Other tumour types
Aside from case-reports, there are no data on the treatment of brain metastases from other tumours than those outlined above. The decision whether or not to provide systemic treatment should therefore be made on an individual basis.

Combination therapy
In the primary treatment of different tumour types (oesophagus, rectum, anus, cervix, head-neck, primary brain glioma), the standard treatment is radiotherapy combined with systemic therapy (chemotherapy and other radiosensitisers). Combination therapy allows for a better response and survival of the primary tumour.

Given the positive effects of the addition of temozolomide to the radiotherapy of primary brain tumours, multiple phase 2 studies have also been conducted on the combination of radiotherapy with temozolomide for patients with brain metastases. This specifically concerns patients with a breast carcinoma, SCLC or NSCLC and a small percentage of remaining primary tumour types. Results of these studies show an acceptable toxicity profile with high response percentages of the combined treatment between 33% and 96%. There is no demonstrated effect on survival (Antonadou, 2002 (27);Verger, 2005 (28)). In a randomised phase 2 study (Antonadou, 2002 (27)), a better objective response (CR and PR) was observed with patients receiving combined temozolomide and WBRT compared to patients only treated with WBRT (96% vs 67%). This difference was not significant given the small patient number. In another randomised phase 2 study (Verger, 2005 (28)), response percentages for WBRT with or without temozolomide were comparable (33%), but a higher percentage persistent remission was seen after 90 days (WBRT with and without temozolomide 17% versus 5%).

The combination of radiotherapy with other chemotherapeutic agents has also been studied, but these studies have been either too small or were non-randomised (Cassier, 2008 (29);Mornex, 2003 (30);Neuhaus, 2009 (31);Guerrieri, 2004 (32)). A definitive conclusion about the effectiveness of these treatments can therefore not be drawn.

A large prospective study with 515 patients with brain metastases from different tumour types randomised patients between WBRT and WBRT with efraproxiral, a haemoglobin analogue. With a median survival of 6.0 (efraproxiral and WBRT) versus 4.4 months (WBRT only), there was no significant difference between the two groups (p=0.07) (Suh, 2006 (33)). A prospective randomised study with WBRT +/- motexafin gadolinium in patients with brain metastases from NSCLC also showed no difference in survival. A non-significant difference in time to neurological decline was observed (10.0 versus 15.4 months, p=0.122), particularly in patients who had a short interval between the treatment with motexafin gadolinium and WBRT (Mehta, 2009 (34)).

Click here for the evidence tables.

References

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Considerations

Non- small cell lung carcinoma (NSCLC)
The majority of patients in the study by Robinet were, in the end, treated with WBRT and it is therefore general practice that patients with symptomatic brain metastases of NSCLC are treated with WBRT. On the basis of the study by Robinet, there are no overriding arguments to deviate from this practice.

Small cell lung carcinoma (SCLC)
Although the follow-up is rather short in the mentioned studies, there are no arguments against administering palliative WBRT simultaneously with the chemotherapy commonly provided for SCLC.

Breast carcinoma
The effectiveness of treating brain metastases from breast carcinoma with chemotherapy only has not been extensively studied. In practice, local treatment is almost always administered (surgery, SRS and/or WBRT).

Combination therapy
No conclusion can be drawn about the effect of adding chemotherapeutic agents other than temozolomide to radiotherapy. The effectiveness of non-chemotherapy radiosensitising agents added to WBRT has not been demonstrated.

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.