Question

Which considerations to determining the best treatment for an individual patient with brain metastases?

Recommendation

The guideline development group is of the opinion that the treatment plan for patients with brain metastases should be discussed by a multidisciplinary oncology / neuro-oncology working group.

Treatment for a patient with brain metastases depends, in part, on the patient's prognosis, prognostic factors specific for the tumour type, the expected effects of treatment and the patient's preferences. The RPA classification is recommended for predicting patients' prognosis: treatment should be considered for RPA classes 1 and 2, and conservative management is generally recommended for patients assigned to RPA class 3 (see Related Appendix 1 for the RPA classification).

Conclusions

The RPA classification is the most commonly used and validated index for the prediction of survival of patients with brain metastases.
Gaspar 1997 (1);Gaspar, 2000 (2);Nieder, 2000 (3)

The GPA and DS-GPA are more recently developed prognostic indices that also include the number of brain metastases and tumour type.
Nieder, 2008 (11);Nieder, 2008 (12);Nieder, 2009 (5);Sperduto, 2008 (13);Sperduto, 2010 (14)

The KPS is the most important factor across the indices of the RPA, the GPA and the DS-GPA.
Gaspar 1997 (1);Sperduto, 2008 (13);Sperduto, 2010 (14)

Literature summary

Patients with brain metastases have a poor prognosis in terms of survival, partly due to extracranial disease activity and partly as a result of the brain metastasis itself. The aim of treatment of brain metastases is, in the first place, to improve or maintain neurological functioning. In a minority of patients, the treatment objectives will also include extension of survival time.

Determining the best treatment for an individual patient with brain metastases is a complex process that requires a multidisciplinary approach. Improving or maintaining quality of life during treatment is usually the main priority for patients. Corticosteroids may improve neurological symptoms in most cases. Study results do not allow for definite conclusions regarding the (extent of) improvement of neurological symptoms (following treatment with corticosteroids) as a result of WBRT (whole brain radiotherapy; see WBRT). There are indications that patients' cognitive functioning may deteriorate after WBRT. However, the decline may in part also be attributed to progression of the brain metastases.

As discussed in WBRTand SRS/neurosurgical resection with or without WBRT, there are hardly any randomised studies that compare the effect of radiotherapy and/or surgery on survival with an untreated control arm. This precludes a definite conclusion on the effect of treatment on the survival of patients with brain metastases.

There are no valid models that allow of reliable prediction as to which patients will or will not benefit from treatment with respect to quality of life. The choice for treatment is therefore generally based on patients' prognosis in terms of survival time. Patients with a poor prognosis do not benefit from extensive treatment, while extensive treatment may extend survival for patients with a relatively good prognosis.

The majority of treated patients receive WBRT, radiosurgery (SRS) or a combination of both, either after surgery or not. Even with treatment, most patients have a limited life expectancy that is expressed in months.

Traditionally, the most commonly used prognostic index is the recursive partitioning analysis (RPA) classification of the Radiation Therapy Oncology Group (RTOG). This classification is based on 4 parameters: age, Karnofsky Performance Status (KPS), presence or absence of extracranial metastases and the status of the primary tumour (Table 1), while being based on data of randomised controlled trials (RCTs) in the USA on the efficacy of WBRT. On the basis of these data, 20% of patients were assigned to RPA class 1, 65% to class 2 and 15% to class 3 (Gaspar, 1997 (1);Gaspar, 2000 (2);Nieder, 2000 (3)).

Table 1. RPA classification

   

Median survival

1-Year survival

Class 1

  • - KPS ≥ 70, age < 65 years
  • - No extracranial metastases
  • - Primary tumour under control

7.1 months

30%

Class 2

All other patients with KPS ≥70

4.2 months

15%

Class 3

All patients with KPS <70

2.3 months

5%

 

Studies with an untreated control arm have not been conducted and the value of the RPA classification as predictive factor (i.e. predictive for treatment efficacy) therefore remains unknown. Furthermore, the RPA classification is based on patient data from RCT's, and these patients generally have a better survival than patients who are treated outside the trial context. Patients from RPA class 1 are generally actively treated, as are most patients in class 2. Symptomatic treatment is usually the treatment chosen for patients in class 3.

Other prognostic factors include the histology of the primary tumour, the patient's gender, serum lactate dehydrogenase, the time interval until occurrence of brain metastases, the number of brain metastases, and neurological deficit (Lagerwaard, 1999 (4);Nieder, 2009 (5);Raizer, 2008 (6)). In addition, specific prognostic factors are distinguished per tumour type, such as receptor status and HER2/neu expression in breast carcinomas (Dawood, 2009 (7);Lin, 2008 (8);Pestalozzi, 2006 (9);Pestalozzi, 2009 (10)).

Six different prognostic indices were compared in a recent study (Nieder, 2009 (5)). Performance status and extracranial tumour activity were identified as important prognostic factors across all indices, whereas the relevance of other factors were rated differently.

A recent new score of the RTOG is the Graded Prognostic Assessment (GPA, Table 2), with four instead of three prognostic classes (Nieder, 2008 (11);Nieder, 2008 (12);Nieder, 2009 (5);Sperduto, 2008 (13)). Scores of the GPA are assigned to patients' age, KPS, the number of brain metastases and the presence of extracranial metastases. The status of the primary tumour is not taken into consideration.

Table 2. Graded prognostic assessment (GPA)

 

Score

0

0.5

1.0

Age

>60

50-59

<50

KPS

<70

70-80

90-100

No. of CNS metastases

>3

2-3

1

Extracranial metastases

Present

-

None

 

On the basis of their GPA score, patients are subdivided into four prognostic groups (Table 3). Patient distribution in the study by Sperduto was as follows: class 1: 10%; class 2: 16%; class 3: 61%; class 4: 13% (Sperduto, 2008 (13)). Like the RPA classification, the GPA classification was developed on the basis of data from patients who were treated with WBRT, and later validated for SRS and surgery (Nieder, 2008 (11);Nieder, 2008 (12)).

Table 3. GPA score and mediane survival

Class

Score

Median survival (months)

1

3.5-4

11.0-18.9

2

3

5.3-9.8

3

1.5-2.5

3.5-5.5

4

0-1

1.9-3.7

 

 

 

 



(Nieder, 2008 (11);Sperduto, 2008 (13))


Notwithstanding the newly developed index of the GPA, the question remains which parameters constitute an ideal index and whether different tumour types may be analysed with the same index (Nieder, 2009 (5)). For this reason, the disease-specific (DS) GPA has been developed in addition to the GPA (Sperduto, 2010 (14)). In the DS-GPA, the original GPA was confirmed for lung carcinomas. Patient's KPS and the number of brain metastases were found to be prognostically significant for melanoma and renal cell carcinoma; for breast carcinoma and gastrointestinal tumours, only the KPS proved important for prognosis. On the basis of the DS-GPA, a breast carcinoma patient with brain metastasis and a KPS of <70 (DS-GPA score 0) has a median survival of 6 months, while a patient with a KPS of 100 (DS-GPA score 4) has a survival of just over 18 months.

The RPA, GPA and DS-GPA demonstrate that there is no definite all-encompassing and validated prognostic index currently available. Together with the KPS, tumour-specific factors are probably the most important factors for predicting patients' prognosis.

References

  1. 1 - Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997 Mar 1;37(4):745-51.
  2. 2 - Gaspar LE, Scott C, Murray K, Curran W. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 2000 Jul 1;47(4):1001-6.
  3. 3 - Nieder C, Nestle U, Motaref B, Walter K, Niewald M, Schnabel K. Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes? Int J Radiat Oncol Biol Phys 2000 Jan 15;46(2):297-302.
  4. 4 - 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.
  5. 5 - Nieder C, Mehta MP. Prognostic indices for brain metastases--usefulness and challenges. Radiat Oncol 2009;4:10.
  6. 6 - Raizer JJ, Hwu WJ, Panageas KS, Wilton A, Baldwin DE, Bailey E, et al. Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features. Neuro Oncol 2008 Apr;10(2):199-207.
  7. 7 - Dawood S, Broglio K, Esteva FJ, Yang W, Kau SW, Islam R, et al. Survival among women with triple receptor-negative breast cancer and brain metastases. Ann Oncol 2009 Apr;20(4):621-7.
  8. 8 - Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 2008 Nov 15;113(10):2638-45.
  9. 9 - Pestalozzi BC, Zahrieh D, Price KN, Holmberg SB, Lindtner J, Collins J, et al. Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol 2006 Jun;17(6):935-44.
  10. 10 - Pestalozzi BC. Brain metastases and subtypes of breast cancer. Ann Oncol 2009 May;20(5):803-5.
  11. 11 - Nieder C, Geinitz H, Molls M. Validation of the graded prognostic assessment index for surgically treated patients with brain metastases. Anticancer Res 2008 Sep;28(5B):3015-7.
  12. 12 - Nieder C, Molls M. Validation of graded prognostic assessment index for patients with brain metastases: in regard to Sperduto et Al. (Int J Radiat Oncol Biol Phys 2008;70:510-514). Int J Radiat Oncol Biol Phys 2008 Dec 1;72(5):1619.
  13. 13 - Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008 Feb 1;70(2):510-4.
  14. 14 - Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010 Jul 1;77(3):655-61.

Considerations

With a lack of proven predictive factors, the decision whether or not to treat brain metastases is mostly determined by the patient's prognosis, the expected benefits of treatment as well as the side effects, and the patient's preferences. Existing classification systems such as the RPA may be used for predicting the prognosis. The more recently developed GPA and DS-GPA allow for a more differentiated prognostic classification. The DS-GPA includes the tumour type, which is an important factor in deciding whether or not to apply treatment in practice. The guideline development group is of the opinion that the RPA should be preferred since this index has been extensively validated and is most commonly applied. However, a decision regarding treatment should not be taken merely on the basis of the RPA classification: patient-specific factors, the number of brain metastases as well as tumour-specific factors should also be considered.

Given the predicted median survival, treatment of brain metastases should be considered for patients assigned to RPA classes 1 and 2, whereas conservative management is recommended for those in RPA class 3.

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.