Question

What are the optimal clinical and radiological diagnostics with respect to extracranial disease activity in case of suspected brain metastasis?

Recommendation

It is recommended to use post-contrast MRI when screening for brain metastases. A post-contrast CT may also be used for logistical reasons, preferably with double dose contrast. The clinical value of additional MRI techniques is still unclear.

It is recommended to conduct a post-operative MRI with and without contrast for patients undergoing resection of a metastasis because further therapy depends on the presence of residual tumour. As post-operative staining makes the assessment more difficult, this post-operative MRI must be performed within 72 hours after the intervention.

Conclusions

An MRI scan with gadolinium-containing contrast is the most sensitive method to detect brain metastases
Schellinger, 1999 (6);Suzuki, 2004 (14);Hochstenbag, 2003 (15);Seute, 2008 (16);Cherryman, 1990 (1);Davis, 1991 (2);Sze, 1990 (3);Grzesiakowska and Tacikowska, 2002 (4);Yuh, 1995 (5);Schellinger, 1999 (6)

A good second choice is a CT scan with a double contrast dose.
Davis, 1991 (2)

A negative CT scan of a patient with neurological symptoms does not exclude brain metastasis and justifies an MRI scan.

FDG PET-CT without intravenous Iodine-containing contrast is unsuitable for the detection or exclusion of brain metastases.
Kitajima, 2008 (17);Yi, 2008 (18)

Literature summary

Aside from the presence or absence of metastases, the number of metastases is also of importance when determining treatment. The following techniques are available (in order of sensitivity): Computed tomography (CT) after administration of intravenous Iodine-containing contrast, MRI and MRI after administration of intravenous gadolinium-containing contrast (Cherryman, 1990 (1);Davis, 1991 (2);Sze, 1990 (3);Grzesiakowska and Tacikowska, 2002 (4);Yuh, 1995 (5);Schellinger, 1999 (6)). It should be noted that imaging without intravenous contrast administration is not considered adequate diagnostic examination; this applies to CT as well as to MRI. If an MRI scan is not available, the CT can be improved through use of a double dose contrast, possibly followed by delayed imaging (Davis 1991 (2)). Sensitivity of a post-contrast MRI may also be increased by administering a double dose contrast or using specific techniques such as magnetisation transfer contrast (MTC) (Mathews, 1997 (7);Yuh 1995 (5); Finelli, 1994 (8);Knauth, 1996 (9);Terae, 2007 (10)). Aside from the sensitivity, a double and triple contrast dose with an MRI also increases the number of false positives (Sze, 1998 (11)). As is the case with CT, a time interval of 10 to 20 minutes between contrast administration and an MRI scan improves the sensitivity of detection, in particular of small metastases (Yuh, 1995 (5);Grzesiakowska and Tacikowska, 2002 (4)). Please consult the relevant guideline [link] for imaging of leptomeningeal metastases.

The sensitivity of a CT scan with contrast for detection of brain metastases in symptomatic patients is approximately 90% (Friedman, 1989 (12);Patchell, 1990 (13)). The sensitivity of CT is lower than that of MRI (Sze, 1990 (3);Schellinger, 1999 (6);Suzuki, 2004 (14)). Other studies have shown that MRI is also more sensitive for detection of asymptomatic metastases (Hochstenbag, 2003 (15);Seute, 2008 (16)), although there are few good comparative studies. It should be noted that advancements in technique have increased the sensitivity of both CT and MRI. The low sensitivity of FDG-Positron Emission Tomography (FDG-PET-CT) without intravenous Iodine-containing contrast renders it unsuitable as a diagnostic modality (Kitajima, 2008 (17);Yi, 2008 (18)).

There are no imaging characteristics that definitively distinguish brain metastases from primary brain tumours or from non-neoplastic abnormalities such as brain abscesses, infections or demyelinating lesions. Brain metastases typically present as ring-shaped enhancing abnormalities surrounded by oedema, located on the subcortical white-grey junction. In the case of multiple lesions, the differential diagnosis will generally pose few problems. The situation is different with solitary abnormalities: in contrast to their sensitivity, the specificity of an MRI or CT scan in case of a single lesion is approximately 80-90% and the proportion of false-positive results is approximately 5-10% (Friedman, 1989 (12);Patchell, 1990 (13)). In the case of a cystic lesion with ring enhancement, diffusion-weighted MRI may provide additional information to distinguish a necrotic tumour from a brain abscess. A brain abscess typically displays a limited diffusion compared to a necrotic metastasis or glioblastoma. However, these findings are not specific (Hartmann, 2001 (19);Desprechins, 1999 (20);Reddy, 2006 (21);Nadal-Desbarats, 2003 (22)). Some sources indicate that Magnetic Resonance Spectroscopy (MRS) may aid in the characterisation of a solitary cerebral lesion, but there is insufficient evidence for this to be incorporated in the present guideline (Hollingworth, 2006 (23)).

Metastasis may not be recognised as such due to an abnormal location or aspect. The absence of enhancement or oedema does not exclude metastasis. Brain metastases may be located in unusual locations, such as: the hypophysis, pineal gland, choroid plexus or dura. Some brain metastases may show bleeding, especially metastases of melanomas, chorio-, lung and renal cell carcinomas. Brain metastases may also have a cystic aspect. Calcifications are very rare but may occur with osteosarcoma and colorectal and ovarian carcinoma metastases. Due to the melanine, brain metastases of a melanoma may display a hyperintense aspect on T1-weighted MRI imaging without contrast administration. The abovementioned considerations warrant a low threshold for conducting a biopsy in case of doubt about the nature of a lesion.

Perfusion- and diffusion-weighted MRI may aid in differentiating between radionecrosis and actual progression in the follow-up of brain metastases after radiotherapy (Kang, 2009 (24)). A recent publication suggests that a T1/T2 mismatch correlates with a radiation effect, and a T1/T2 match correlates with a local recurrence. The sensitivity for identification of necrosis was 83% in this study, with a specificity of 91% (Kano, 2010 (25)). Follow-up studies are needed to assess the clinical applicability of this method.

References

  1. 1 - Cherryman G, Olliff J, Golfieri R. A prospective comparison of Gd-DTPA-enhanced MRI and contrast-enhanced CT-scanning in the detection of brain metastasis arising from small cell lung cancer. 1990.
  2. 2 - Davis PC, Hudgins PA, Peterman SB, Hoffman JC, Jr. Diagnosis of cerebral metastases: double-dose delayed CT vs contrast-enhanced MR imaging. AJNR Am J Neuroradiol 1991 Mar;12(2):293-300.
  3. 3 - Sze G, Milano E, Johnson C, Heier L. Detection of brain metastases: comparison of contrast-enhanced MR with unenhanced MR and enhanced CT. AJNR Am J Neuroradiol 1990 Jul;11(4):785-91.
  4. 4 - Grzesiakowska U, Tacikowska M. An assessment of the effectiveness of magnetic resonance imaging in delayed sequences after administration of Gd-DTPA contrast in the detection of metastatic lesions in the brain. Med Sci Monit 2002 Jan;8(1):MT21-MT24.
  5. 5 - Yuh WT, Tali ET, Nguyen HD, Simonson TM, Mayr NA, Fisher DJ. The effect of contrast dose, imaging time, and lesion size in the MR detection of intracerebral metastasis. AJNR Am J Neuroradiol 1995 Feb;16(2):373-80.
  6. 6 - Schellinger PD, Meinck HM, Thron A. Diagnostic accuracy of MRI compared to CCT in patients with brain metastases. J Neurooncol 1999;44(3):275-81.
  7. 7 - Mathews VP, Caldemeyer KS, Ulmer JL, Nguyen H, Yuh WT. Effects of contrast dose, delayed imaging, and magnetization transfer saturation on gadolinium-enhanced MR imaging of brain lesions. J Magn Reson Imaging 1997 Jan;7(1):14-22.
  8. 8 - Finelli DA, Hurst GC, Gullapali RP, Bellon EM. Improved contrast of enhancing brain lesions on postgadolinium, T1-weighted spin-echo images with use of magnetization transfer. Radiology 1994 Feb;190(2):553-9.
  9. 9 - Knauth M, Forsting M, Hartmann M, Heiland S, Balzer T, Sartor K. MR enhancement of brain lesions: increased contrast dose compared with magnetization transfer. AJNR Am J Neuroradiol 1996 Nov;17(10):1853-9.
  10. 10 - Terae S, Yoshida D, Kudo K, Tha KK, Fujino M, Miyasaka K. Contrast-enhanced FLAIR imaging in combination with pre- and postcontrast magnetization transfer T1-weighted imaging: usefulness in the evaluation of brain metastases. J Magn Reson Imaging 2007 Mar;25(3):479-87.
  11. 11 - Sze G, Johnson C, Kawamura Y, Goldberg SN, Lange R, Friedland RJ, et al. Comparison of single- and triple-dose contrast material in the MR screening of brain metastases. AJNR Am J Neuroradiol 1998 May;19(5):821-8.
  12. 12 - Friedman WA, Sceats DJ, Jr., Nestok BR, Ballinger WE, Jr. The incidence of unexpected pathological findings in an image-guided biopsy series: a review of 100 consecutive cases. Neurosurgery 1989 Aug;25(2):180-4.
  13. 13 - Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990 Feb 22;322(8):494-500.
  14. 14 - Suzuki K, Yamamoto M, Hasegawa Y, Ando M, Shima K, Sako C, et al. Magnetic resonance imaging and computed tomography in the diagnoses of brain metastases of lung cancer. Lung Cancer 2004 Dec;46(3):357-60.
  15. 15 - Hochstenbag MM, Twijnstra A, Hofman P, Wouters EF, ten Velde GP. MR-imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment? Lung Cancer 2003 Nov;42(2):189-93.
  16. 16 - Seute T, Leffers P, ten Velde GP, Twijnstra A. Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus MRI). Cancer 2008 Apr 15;112(8):1827-34.
  17. 17 - Kitajima K, Murakami K, Yamasaki E, Fukasawa I, Inaba N, Kaji Y, et al. Accuracy of 18F-FDG PET/CT in detecting pelvic and paraaortic lymph node metastasis in patients with endometrial cancer. AJR Am J Roentgenol 2008 Jun;190(6):1652-8.
  18. 18 - Yi CA, Shin KM, Lee KS, Kim BT, Kim H, Kwon OJ, et al. Non-small cell lung cancer staging: efficacy comparison of integrated PET/CT versus 3.0-T whole-body MR imaging. Radiology 2008 Aug;248(2):632-42.
  19. 19 - Hartmann M, Jansen O, Heiland S, Sommer C, Munkel K, Sartor K. Restricted diffusion within ring enhancement is not pathognomonic for brain abscess. AJNR Am J Neuroradiol 2001 Oct;22(9):1738-42.
  20. 20 - Desprechins B, Stadnik T, Koerts G, Shabana W, Breucq C, Osteaux M. Use of diffusion-weighted MR imaging in differential diagnosis between intracerebral necrotic tumors and cerebral abscesses. AJNR Am J Neuroradiol 1999 Aug;20(7):1252-7.
  21. 21 - Reddy JS, Mishra AM, Behari S, Husain M, Gupta V, Rastogi M, et al. The role of diffusion-weighted imaging in the differential diagnosis of intracranial cystic mass lesions: a report of 147 lesions. Surg Neurol 2006 Sep;66(3):246-50.
  22. 22 - Nadal DL, Herlidou S, de MG, Gondry-Jouet C, Le GD, Deramond H, et al. Differential MRI diagnosis between brain abscesses and necrotic or cystic brain tumors using the apparent diffusion coefficient and normalized diffusion-weighted images. Magn Reson Imaging 2003 Jul;21(6):645-50.
  23. 23 - Hollingworth W, Medina LS, Lenkinski RE, Shibata DK, Bernal B, Zurakowski D, et al. A systematic literature review of magnetic resonance spectroscopy for the characterization of brain tumors. AJNR Am J Neuroradiol 2006 Aug;27(7):1404-11.
  24. 24 - Kang TW, Kim ST, Byun HS, Jeon P, Kim K, Kim H, et al. Morphological and functional MRI, MRS, perfusion and diffusion changes after radiosurgery of brain metastasis. Eur J Radiol 2009 Dec;72(3):370-80.
  25. 25 - Kano H, Kondziolka D, Lobato-Polo J, Zorro O, Flickinger JC, Lunsford LD. T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. Neurosurgery 2010 Mar;66(3):486-91.
  26. 26 - Albert FK, Forsting M, Sartor K, Adams HP, Kunze S. Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 1994 Jan;34(1):45-60.
  27. 27 - Cairncross JG, Pexman JH, Rathbone MP, DelMaestro RF. Postoperative contrast enhancement in patients with brain tumor. Ann Neurol 1985 Jun;17(6):570-2.
  28. 28 - Jeffries BF, Kishore PR, Singh KS, Ghatak NR, Krempa J. Contrast enhancement in the postoperative brain. Radiology 1981 May;139(2):409-13.

Considerations

Post-operative enhancement makes evaluation more difficult and post-operative MRI should therefore be performed within 72 hours after the intervention. On a sidenote, this effect has only been demonstrated with CT (Albert, 1994 (26);Cairncross, 1985 (27);Jeffries, 1981 (28)).

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.