Consensus recommendations for a standardized brain tumor imaging protocol for clinical trials in brain metastases

Abstract

A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.

Need for Development of Therapeutics for Treating Brain Metastases

Brain metastases are the most common central nervous system (CNS) tumor,^1,2 with more than 150 000–200 000 new patients diagnosed with brain metastases each year in the US.^3,4 This incidence is substantially greater than that of primary malignant brain tumors.⁵ The lifetime incidence of brain metastases among all cancer patients is approximately 10–30%.^2,6,7 The most common primary tumors are lung cancer, breast cancer, and melanoma, occurring in approximately 40–50%, 15–20%, and 5–20%, respectively, of newly diagnosed brain metastasis patients,⁸ with melanoma having the highest predilection to metastasize to the brain (~50%).^9,10 The incidence of brain metastases appears to be increasing, in part due to an overall increase in primary cancers, as well as better systemic therapies, which increase the probability of metastatic disease as patients live longer, especially within the brain as a potential sanctuary protected by the blood–brain barrier.²

The discovery of brain metastases has always been very sobering, indicating disseminated malignancy and historically a dismal prognosis. However, hope is increasing at the dawn of the molecular and immunotherapeutic era, with improved local therapies such as stereotactic radiosurgery (SRS) and earlier detection of brain metastases while patients have good performance status.^11,12 Improvements in outcome for patients with brain metastases from lung cancer, breast cancer, and melanoma have all been reported, and for certain patient subsets, survival is substantially longer than historical estimates. For instance, the success of monoclonal antibodies against immune checkpoints in some cases of advanced melanoma and non-small-cell lung carcinoma (NSCLC)^13–15 gives hope for further advances with immunotherapy. Durable responses have been reported with targeted agents, including BRAF inhibitors in melanoma and other cancers, anaplastic lymphoma kinase (ALK) inhibitors in ALK+ NSCLC, and human epidermal growth factor receptor 2 (HER2) inhibitors in HER2+ breast cancer.^16–18 Other clinical trials for CNS metastases with newer targeted therapies (eg, NCT03994796) and multiple immunotherapies are currently in progress (eg, NCT02886585, NCT02939300). Use of SRS for multiple brain metastases is also rising, particularly following the results of the Alliance N0574¹⁹ and N107C²⁰ trials with greater community health care penetrance of SRS. That being said, it is clear that much work still needs to be done, as prognosis following the diagnosis of brain metastasis is still often enumerated in months,^3,21,22 underscoring the need for continued development of therapeutic options for patients with brain metastases.

Need for Imaging Standardization for Improved Therapeutic Response Assessment in Brain Metastases

With new efforts at treating brain metastases in an era when the vast majority of patients are diagnosed and monitored using MR imaging, reliable methods for disease monitoring and response assessment using MR imaging data are needed. Particularly in the conduct of clinical trials, implementation of standardized brain MRI protocols is an essential first step toward achieving consistent measurement and reliable assessment of response to novel therapies, whether response is assessed using clinical response criteria or automated approaches. Such a standardized brain tumor imaging protocol (BTIP) has already been developed²³ for gliomas and is being widely adopted in glioma trials. Based on the experiences of implementing the BTIP protocol, it has become apparent that MRI protocols for clinical trials must generally also serve the function of a routine clinical MRI for standard-of-care management of patients in order to minimize duplicative imaging sessions for patients and avoid challenges with reimbursement.

A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing the development of therapeutics for CNS metastases. At this meeting, the need for more consistent response assessment methodology for brain metastases was identified as a key issue, and the first step toward consistent, reliable response assessment is the standardization of image acquisition with an MRI protocol that could be implemented in the multicenter setting.

The multidisciplinary and multinational Response Assessment in Neuro-Oncology–Brain Metastases (RANO-BM) working group has developed standardized guidelines for determining response to therapy for brain metastases.^24–26 This group has provided a consensus approach to measuring brain metastases and incorporating corticosteroid dosing and clinical status into the response assessment criteria.²⁴ The difficult issues of response assessment following SRS and immunotherapy were also broached by this group; they stated that advanced imaging may assist in discriminating tumor progression from treatment effect in these posttreatment circumstances while acknowledging that to date, these advanced imaging techniques have not shown robust validation to justify the recommendation of any particular advanced imaging technique(s) for this purpose.²⁴ Finally, a supplementary appendix to the RANO-BM manuscript²⁴ gives a recommended minimum MRI protocol for imaging brain metastases.

However, particularly as clinical trials for brain metastases increase, and MRI technology evolves, an updated minimum recommended protocol for imaging brain metastases in clinical trials is needed. In this current effort, we use the RANO-BM appendix²⁴ and the similar BTIP²³ as a core of such a revised protocol, which we hope will provide meaningful and generalizable imaging data from clinical trials and which may also facilitate standard-of-care clinical evaluation and decision making.

Magnetic Resonance Imaging of Brain Metastases

The early detection of brain metastases leads to earlier interventions and has been shown to result in better quality of life.^27,28 Treatment strategies (eg, SRS vs whole brain radiation) are often based on the number and size of metastases,²⁹ and thus accurate imaging of brain metastases is crucial. Multiple brain metastases are common with many primary tumor histologies, though solitary metastases may be seen with some cancers.^30,31 Brain metastases are distributed proportional to blood flow, with 80% in the cerebral hemispheres, 15% in cerebellum, and 5% in the brainstem.^32,33 Brain metastases commonly occur at the interface between gray and white matter, possibly due to the change in size of arterioles from cortex to white matter.³⁴ However, they also occur purely within white matter as well as within cortex and deep gray matter structures.

The diagnosis of brain metastases is typically made with gadolinium-based contrast-enhanced MRI, which is superior to contrast-enhanced CT.^35–38 Prior to 2006, treatment guidelines for brain metastases were based upon studies in which metastases were diagnosed and monitored with CT.^39–41 However, the value of gadolinium-based contrast-enhanced T1-weighted imaging for the detection of brain metastases has been well documented for more than 30 years.^42–46 Almost all brain metastases enhance in their entirety, due to the lack of blood–brain and blood–tumor barriers,³⁴ unless the tumors have non-enhancing cystic or frankly hemorrhagic components. Brain metastases of moderate to large size are typically surrounded by substantial vasogenic edema, related to increased tumor capillary permeability and/or temporary vascular occlusion from neoplastic cell growth after hematological spread.³⁴ Small metastases can also present with disproportionate peritumoral edema. T2-weighted imaging and T2-weighted fluid attenuated inversion recovery (FLAIR) best detect the T2 prolongation associated with this edema in the brain. Metastases themselves vary in signal intensity on T2-weighted imaging and, while usually relatively hyperintense,³⁴ may be hypointense, classically associated with highly cellular neoplasms with high nuclear-to-cytoplasm ratios and with some, though not all, adenocarcinoma metastases.^34,47–49 Calcified metastases are rare but possible. Metastases vary in apparent diffusion coefficient (ADC) and appearance on diffusion-weighted imaging (DWI), and attempts have been made to correlate ADC with tumor histology and response to therapy such as SRS with limited success.^50–52

Baseline MR Evaluation

For response assessment using the current standardized response criteria, brain metastases must be accurately measurable in at least one dimension.²⁴ Thin-section, preferably volumetric, T1-weighted imaging would be most desirable. Identical pre- and post-contrast T1-weighted imaging allows the subtraction of inherent T1 shortening or bright signal, which may be seen in hemorrhage (methemoglobin) from true contrast enhancement and can aid in clinical evaluation and advanced image post-processing for trials. Hemorrhage within brain metastases correlates with certain histologies (being particularly common in melanoma, renal cell carcinoma, choriocarcinoma, and thyroid carcinoma but also common in breast and lung carcinoma) and with increasing size. Overall, approximately 20% of metastases may be overtly hemorrhagic,^34,53 with two-thirds of large metastases showing evidence of hemorrhage on susceptibility weighted imaging (SWI).⁵⁴ Additionally, melanoma metastases can have T1 shortening from melanin. Therefore, a means to account for pre-contrast T1 hyperintensity in evaluating contrast enhancement is important. Pre- and post-contrast image subtraction also markedly improves contrast ratios of enhancing lesions.⁵⁵

Improved Detection of Brain Metastases

The question of which post-contrast T1-weighted pulse sequence is “best” is complicated. The first limitations in answering this question relate to what MR scanner hardware and software a particular site possesses, including field strength (usually 1.5T vs 3T)—3T brain MRI offers signal-to-noise ratio (SNR) advantages over 1.5T, which can be traded off for better spatial resolution or decreased imaging time.^56–58 Any disadvantages of 3T are probably offset by its advantages when imaging brain metastases.^59,60 For instance, 3D fast spin echo T1-weighted techniques such as CUBE (GE Healthcare), SPACE (Sampling Perfection with Application optimized Contrasts by using different flip angle Evolutions; Siemens Healthcare), and VISTA (Volumetric Isotropic TSE Acquisition; Philips Healthcare)⁶¹ are all improved in SNR at 3T compared with 1.5T.

Magnetization prepared (“IR-prepped”) 3D gradient recalled echo (GRE) pulse sequences such as MPRAGE (magnetization-prepared rapid acquisition with gradient echo), IR-SPGR (inversion recovery–spoiled gradient), BRAVO (Brain Volume Imaging), TFE (turbo field echo), and 3D Fast FE (field echo) are robust, high signal-to-noise, T1-weighted pulse sequences with exquisite anatomical depiction, which are very widely available in community and academic imaging centers at both 1.5T and 3T field strengths. They form the backbone of the BTIP protocol²³ and are featured in the minimum standard protocol for brain metastases recommended in this publication. As these are 3D series, orthogonal reformats can and should be created from them, and image review should be performed in axial, sagittal, and coronal planes. However, there are disadvantages of post-contrast IR-GRE pulse sequences. The contrast enhancement of brain lesions is slightly less conspicuous with spoiled GRE-based pulse sequences than with spin echo (SE)–based pulse sequences.^62,63 The relatively bright white matter of IR-GRE yields good gray-white differentiation and depiction of anatomy, but a brightly enhancing metastasis on bright white matter then becomes less conspicuous, having a lower contrast ratio (Fig. 1). In comparison, SE-based pulse sequences including the 3D turbo SE (TSE) T1-weighted SPACE/CUBE/VISTA have relatively lower signal intensity in white matter, in part due to magnetization transfer effects,⁶⁴ increasing the contrast ratio of enhancing metastases within white matter (Fig. 1). Indeed, Knauth et al reported equivalent enhancing lesion conspicuity relative to white matter using magnetization transfer (by applying an off-resonance radiofrequency pulse to suppress background tissue signal) SE T1-weighted imaging and a single dose of gadolinium, when compared with no magnetization transfer and triple-dose gadolinium.⁶⁵ IR-GRE pulse sequences with “bright blood” contrast also make normal cortical vessels much more prominent than with SE-based pulse sequences, which have greater inherent flow suppression. (Three-dimensional TSE sequences like SPACE and CUBE have inherent flow suppression based on two mechanisms: [i] uncompensated gradient moments in the echo train which introduce intravoxel dephasing and [ii] stimulated echoes from non-180° variable flip angles which induce dephasing.) In cross section, these normal cortical vessels appear as innumerable bright dots, which can hinder the distinction of peripheral subcentimeter enhancing metastases, despite relatively high lesion SNR. Lastly, unlike with SE-based pulse sequences, it is not feasible to fat saturate IR-GRE pulse sequences, and so enhancing osseous metastases may be indistinguishable within the normally fat containing, T1-bright skull, skull base, and upper cervical vertebral marrow.

Fig. 1.

Comparison of 3D IR-GRE (A, C) and 3D TSE (B, D) T1-weighted imaging in a patient with metastatic lung carcinoma to the brain. Larger lesions (eg, right posterior frontal, white arrows, A and B) are well visualized with both techniques. Smaller lesions (eg, right posterior temporal, black arrows, C and D) may be better visualized with 3D TSE T1-weighted imaging due to more native vascular signal suppression and higher contrast:noise ratio relative to underlying brain.

Previous studies found superior detection of brain metastasis with 3D fast spoiled gradient echo (FSPGR) or MPRAGE (with 1–1.4 mm slice thickness) compared with thick section (6–7 mm) 2D SE imaging.^63,66,67 However, a 2016 meta-analysis⁶⁸ which included 5 studies^64,69–72 comparing 3D TSE T1 (eg, SPACE) and 3D MPRAGE with equal slice thickness (1 mm) found superior detection of small metastases with 3D TSE, although these 5 studies were performed at 3T field strength only. These results are supported by other published data. Chappell et al demonstrated greater post-contrast lesion conspicuity with SE compared with GRE imaging.⁷³ Majigsuren et al found higher contrast-to-noise ratio (CNR) within a sampling of various brain tumors with T1-weighted CUBE (3D TSE) compared with 3D FSPGR at 3T, despite performing the post-contrast CUBE prior to the FSPGR in all instances.⁷⁴ Kammer et al reported significantly higher detectability of contrast-enhancing brain tumors with 3D TSE compared with MPRAGE at 3T with regard to number of lesions identified (particularly if small) as well as superiority of 3D TSE with regard to CNR and diagnostic confidence.⁷⁵ Danieli et al reported higher contrast rate, CNR, and visual conspicuity among metastases and gliomas with SPACE and VIBE relative to MPRAGE, and more accurate size and morphology estimates with SPACE in a 3T study.⁷⁶ Kim et al reported approximately double the detection rates of ≤5 mm brain metastases with a black blood vascular suppression (delay alternating with nutation for tailored excitation [DANTE]) version of SPACE compared with MPRAGE as well as higher CNR of metastases and shorter reading time with DANTE SPACE.⁷⁷ Similar to 2D TSE, 3D TSE T1-weighted images can be fat saturated, an advantage in detecting osseous metastases, unlike IR-GRE techniques like MPRAGE and BRAVO. However, 3D TSE is more challenging to acquire at 1.5T due to lower SNR. Although more recent iterations of 1.5T T1-weighted TSE seem to have acceptable SNR and lesion conspicuity, published literature for detection of brain metastases is currently still lacking. Three-dimensional TSE also may not have been a stock MRI pulse sequence with relatively older scanner purchases, and therefore, imaging centers may require an additional cost to install the sequence. It is also not standardized among MR vendors. There is not a motion-compensated version of 3D TSE, which is therefore susceptible to motion artifacts. Additionally, 3D TSE cannot be used with metallic SRS immobilization frames because eddy currents arise in the frame due to the long echo trains; GRE pulse sequences are therefore used for SRS targeting.⁷⁸

It is also important to recognize in this discussion of ideal post-contrast T1-weighted imaging that much of the published data are concerned with the issue of metastasis detection rather than measurement. Published data on variability of measurements of brain metastases are limited.⁷⁹

In summary, for post-contrast T1-weighted imaging, the universal availability of IR-GRE pulse sequences and their many strengths support their use in a standardized brain metastasis imaging protocol, but their limitations in identifying small metastases and osseous metastases promote the recommendation that sites also include an SE or TSE post-gadolinium T1-weighted pulse sequence, with fat suppression where possible to aid in identifying osseous metastases. The ideal choice for this pulse sequence at 3T would be 3D TSE such as CUBE, SPACE, or VISTA, which should also be fat saturated for better evaluation of osseous metastases, if available. (This sequence would effectively replace the 3D T1-weighted IR-GRE sequence.) If not available, an axial and/or coronal or 3D T1-weighted FLAIR could be considered at 3T,^55,80–82 where the inversion pulse helps null cerebrospinal fluid at 3T. At 1.5T, adding an axial and/or coronal T1-weighted SE series may increase accuracy and diagnostic confidence for small brain metastases. Disadvantages of T1-weighted SE imaging to keep in mind include ghosting artifacts due to strong signal enhancement in flowing blood, especially in the posterior fossa from the dural venous sinuses, and thicker image slices.

Other considerations for the detection of small metastases include the choice of gadolinium-based contrast agent (GBCA), its dose, and the timing of imaging following i.v. administration. High relaxivity (r1) GBCA,^83–87 double- or triple-dose GBCA,^88–97 or increased delay time, particularly with IR-GRE pulse sequences,^89,98,99 may lead to greater sensitivity for small metastases. However, some concern over gadolinium deposition in the body¹⁰⁰ and nephrogenic systemic fibrosis¹⁰¹ has led to constraints in GBCA dosing at some local institutions, and so we provide a protocol using single-dose GBCA administration. Since delayed imaging after GBCA administration is not practical for many institutions, we do not give a uniform recommendation for an additional delay after i.v. administration of GBCA other than that introduced by performance of T2-weighted and (optional) dynamic susceptibility contrast (DSC) perfusion-weighted MRI after GBCA administration and before post-contrast T1-weighted imaging. The time interval between GBCA administration and post-contrast T1-weighted imaging can impact lesion conspicuity and apparent lesion size,^89,102 and should therefore be standardized. In our suggested protocol, the delay time will be made uniform through the inclusion of DSC-MRI and T2-weighted imaging between i.v. GBCA administration and post-contrast 3D T1-weighted imaging.

Finally, in post-processing or live image review, clinicians may also benefit from reviewing 3D post-contrast T1-weighted image sets with overlapping maximum intensity projections (eg, 10 mm sections reconstructed at 4 mm intervals), which may help with accuracy and speed of image review for small metastases.¹⁰³

When evaluating for osseous metastases, fat-saturated T2-weighted and T2-weighted FLAIR images, at least one post-contrast T1-weighted series, and DWI are helpful. Leptomeningeal metastases may be better evaluated with post-contrast T2-weighted FLAIR than some post-contrast T1-weighted imaging,¹⁰⁴ which though not included in this basic protocol could be added for suspected or known leptomeningeal metastasis. Post-contrast 3D TSE T1-weighted imaging with its relative vascular signal suppression is also useful for leptomeningeal metastasis detection.¹⁰⁵ We also refer the reader to the RANO Leptomeningeal Response Assessment group’s recommendations for leptomeningeal metastasis.^106,107

Stereotactic Radiosurgery and Radiation Necrosis

Many brain metastases are now treated with SRS, and many if not all clinical trials for brain metastases allow for SRS. This introduces the particular challenge of response assessment for enlarging, contrast-enhancing lesions following SRS.^108,109 Approximately one-third of treated metastases will increase in size on contrast-enhanced MRI following SRS,¹¹⁰ and this could represent progressive tumor and/or radiation injury, as radiation necrosis is not uncommon following SRS. This translates to roughly half of SRS-treated patients experiencing an enlarging contrast-enhancing lesion.¹¹⁰ The incidence of radiation injury/necrosis depends upon the radiation dose utilized, the volume of the target lesion, and the means by which radiation necrosis is determined, but has been estimated at 6–26%.^21,111 However, it has been estimated to be as high as 60% cumulative risk for larger lesions¹¹¹ and may be higher for patients also treated with immunotherapy.¹¹² Radiation necrosis typically occurs 3–18 months after SRS but can occur up to 3 years post-SRS.²¹ However, conventional MRI poorly differentiates between radiation necrosis and tumor or an admixture of the two,^113,114 and alternative methods using tumor segmentation¹¹⁵ or delayed imaging¹¹⁶ are time intensive and may be difficult to routinely employ in clinical care. Admixture of tumor and necrosis is not uncommon following SRS¹⁰⁹ and further complicates diagnosis.

Investigators have pursued “advanced” or physiologic/mechanistic MRI techniques, as well as other imaging modalities such as PET, to help discriminate between radiation necrosis and recurrent tumor. DWI and ADC,^117–119 MR spectroscopy,^120,121 arterial spin labeling (ASL),¹²² dynamic contrast-enhanced (DCE) MRI,^{119,123–125} and DSC-MRI^{119,126–128} have all been evaluated in this clinical context, as have thallium-201 single-photon emission CT,^122,12918F-FDG PET (fluorodeoxyglucose), and amino acid PET (¹¹C-methionine, ¹⁸F-fluorodopa, ¹⁸F-fluoro-ethyltyrosine, ¹⁸F-fluorocholine).^130–138 Each of these techniques has some merit as well as unique challenges. None has been validated in multicenter trials of brain metastases treated with SRS. Some of these techniques also produce findings which may predictably evolve over time following SRS, complicating their interpretation.¹³⁹ Amino acid PET, with its low background activity in the brain, has particular promise for evaluating brain malignancies, but it is not FDA approved for brain metastases. Relatedly, it is not generally reimbursable in the United States, which makes it difficult to universally recommend. However, for trials involving other parts of the world such as Europe for which amino acid PET may be more feasible, it should certainly be considered for response assessment post-SRS.¹⁴⁰ Delayed contrast extravasation MRI with TRAMs (treatment response assessment maps) has also been used and shows promise,^116,141,142 including with T1 mapping and subtraction,¹⁴³ though this requires scanning at both 5 minutes and again at 60–105 minutes after i.v. GBCA administration. This may not be practical for a protocol standardized for use across many institutions and requires specific software for its analysis, but investigators could consider this if it is feasible for their sites. Future means of imaging discrimination of radiation necrosis and viable tumor could include texture analysis¹⁴⁴ and deep learning.¹⁴⁵

DWI is included in the standardized protocols, as it was for the BTIP protocol,²³ for a few reasons. It is often included in any brain MRI, given the unique information it provides with regard to unanticipated pathology such as infarction or abscess. It can suggest tumor cellularity. It is a very fast pulse sequence, requiring only on the order of a minute of MR gradient time, and so it does not cost much to perform. Last, as DWI has been^117–119 and will likely continue to be used in clinical investigations of brain tumor response assessment, we provide it for investigators in the standardized protocols.

We encourage the use of DSC-MRI (which requires an i.v. bolus administration of GBCA) in the standardized brain metastasis imaging protocol because it may help differentiate tumor progression, characterized by higher blood volume and lower percentage signal recovery, from radiation necrosis in the post-SRS radiation treatment setting.^126–128 However, given the lack of validation of DSC-MRI for this purpose in multicenter trials, we encourage investigators to decide whether or not to mandate DSC-MRI within their own clinical trial contexts. DSC-MRI is widely available, technically robust, relatively short in acquisition time (typically on the order of 2–3 minutes), and requires no additional GBCA beyond that given for conventional post-contrast imaging. DSC-MRI requires less MRI gradient time and has substantially higher signal to noise than DCE-MRI, making it easier for a wide variety of imaging sites to perform. Based on recent computer simulations and in vivo studies, it has been suggested that DSC-MRI using a single-dose bolus of GBCA without preload, in combination with a low (eg, 30 degrees) flip-angle and post-processing leakage correction which mitigates the effect of GBCA extravasation in contrast-enhancing tumors, is an efficacious DSC-MRI protocol requiring only a single dose of GBCA.^146–148 This would be advantageous given that concerns about nephrogenic systemic fibrosis¹⁰¹ and gadolinium deposition in other tissues including the brain¹⁰⁰ have made some centers reluctant to use supra-standard (ie, >0.1 mmol/kg) doses of gadolinium. Importantly, particularly for studies which may perform quantitative analysis of DSC-MRI, parallel imaging is advised with DSC-MRI to minimize distortion.

Interpretation of DSC-MRI for brain metastases post-SRS is beyond the scope of this effort, but suffice it to say that it should be used with caution and some skepticism in clinical practice. Indeed, published data in this setting are limited to single-institution studies; its implementation and analysis are very technique dependent,¹⁴⁹ and the timing of DSC relative to SRS and trends in DSC metrics over time probably matter. Generally speaking, increased blood volume and relatively low percentage signal recovery are concerning for recurrent tumor rather than radiation necrosis.^126–128 We do note that smaller lesions and peripherally located lesions near higher baseline cortical perfusion and cortical vessels are more difficult to evaluate with DSC perfusion.

Immunotherapy and Brain Metastasis Imaging

Immunotherapy has had remarkable success in different settings, including recent clinical trials demonstrating promising response rates in brain metastases from melanoma, increasing its investigation across brain metastases from many histologies. Because it purposefully stimulates a host immune reaction against tumor, it can create “pseudoprogressive” contrast enhancement due to inflammatory response rather than recurrent metastases. This creates a challenge for response assessment, which has been addressed by the RANO immunotherapy (iRANO) criteria.¹⁵⁰ In summary, if radiologic progression is seen within 6 months of immunotherapy, it is advised that patients remain on immunotherapy (if no clinical contraindication) for 3 months, at which time repeat imaging can be used to judge whether this represents true progressive disease.¹⁵⁰ Research into whether advanced imaging techniques could distinguish between pseudo- and true progression earlier in this process has only just begun.¹⁵¹

Recommended Protocol(s)

The recommended MRI protocol for use in evaluating brain metastases is highly dependent on the scanner performance and capabilities at the specific sites. A flowchart to guide decision making in terms of the recommended protocol(s) is illustrated in Fig. 2. Ideally, if sites are able to use a 3T MRI scanner and are able to perform 3D T1-weighted TSE, they should replace the 3D T1-weighted IR-GRE sequence both before and after i.v. GBCA administration (Table 1). Additionally, as a large proportion of patients receive SRS for brain metastases, we encourage but do not mandate the inclusion of DSC perfusion MRI as part of a protocol for clinical trials as it can provide complementary information to distinguish tumor progression from treatment effect in any enlarging contrast-enhancing lesion post-SRS. DSC-MRI is brief, requires no additional GBCA, and should be easily acquired at any imaging center. It will not always be helpful in distinguishing between tumor progression and radiation necrosis, but sometimes the longitudinal changes provided may. We give updated suggestions for DSC-MRI pulse sequence parameters as part of the ideal 3T protocol in Table 1. Tables 2 and 3 provide minimum standard recommended imaging parameters for evaluation of brain metastases at 3T and 1.5T, respectively. These minimum protocols include imaging series that will be familiar to current users of the BTIP.

Fig. 2.

Metastatic brain tumor imaging protocol decision-making flow chart. If sites are using a 3T MRI scanner and have 3D TSE available, they should use Table 1 (ideal recommended 3T protocol). If sites are using a 3T MRI scanner and do not have 3D TSE, they should use Table 2 (minimum standard 3T protocol). If sites use a 1.5T scanner, they should use Table 3 (minimum standard 1.5T protocol). Note that DSC perfusion may be used with the minimum standard protocols at 3T and 1.5T as well as with the “ideal” 3T protocol.

Table 1.

“Ideal” recommended 3T metastatic brain tumor imaging protocol

	3D T1w TSE Preb	Ax 2D FLAIRj,q	Ax 2D DWIp,v		DSCa Perfusion (Optional)	Ax 2D T2wh,i,q	3D T1w TSE Postb
Sequence	TSEs	TSEc,s	SS-EPIg	Contrast Injection a	GE-EPI	TSEc,s	TSEs
Plane	Sagittal or Axial	Axial	Axial		Axial	Axial	Sagittal or Axial
Mode	3D	2D	2D		2D	2D	3D
TR [ms]	550–750	>6000	>5000		1000–1500	>2500	550–750
TE [ms]	Min	100–140	Min		25–35 ms	80–120	Min
TI [ms]		2000–2500k
Flip angle	Defaultt	90º/≥160º	90º/180º		30º	90º/≥160º	Defaultt
Frequency	256	≥256	128		≥96	≥256	256
Phase	256	≥256	128		≥96	≥256	256
NEX	≥1	≥1	≥1		1	≥1	≥1
FOV	256 mm	240 mm	240 mm		240 mm	240 mm	256 mm
Slice thickness	1 mm	3 mm	3 mm		3–5 mm as needed to cover tumor	3 mm	1 mm
Gap/spacing	0	0	0		0–1 mm as needed to cover tumor	0	0
Other options			b = 0, 500, 1000 s/mm2 ≥3 directions		30–60 pre-bolus time points; >120 total time points
Parallel imaging	Up to 3xu	Up to 2x	Up to 2x		Up to 2x	Up to 2x	Up to 3xu

Abbreviations: TR = repetition time; TE = echo time; TI = inversion time; NEX = number of excitations; FOV = field of view.

^a 0.1 mmol/kg dose injection with a gadolinium chelated contrast agent. Use of a power injector is desirable at an injection rate of 3–5 cc/sec. (Note: If DSC perfusion is collected, contrast injection is performed after starting DSC acquisition. DSC perfusion can be performed with the “ideal” protocol at 3T as well as with the minimum standard protocols at 3T and 1.5T.)

^b Post-contrast 3D T1-weighted images should be collected with equivalent parameters to pre-contrast 3D T1-weighted images.

^c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, Toshiba).

^d FL2D = two-dimensional fast low angle shot (FLASH; Siemens) is equivalent to the spoil gradient recalled echo (SPGR; GE) or T1- fast field echo (FFE; Philips), fast field echo (FastFE; Toshiba), or the radiofrequency spoiled steady state acquisition rewound gradient echo (RSSG; Hitachi). A fast gradient echo sequence without inversion preparation is desired.

^e IR-GRE = inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled gradient-echo (IR-SPGR or Fast SPGR with inversion activated or BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba).

^f A 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE or another IR-prepped 3D T1-weighted sequences and therefore should be avoided.

^g In the event of significant patient motion, a radial acquisition scheme may be used (eg, BLADE [Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, this acquisition scheme is can cause significant differences in ADC quantification and therefore should be used only if EPI is not an option. Further, this type of acquisition takes considerable more time.

^h Dual echo PD/T2 TSE is optional for possible quantification of tissue T2. For this sequence, PD is recommended to have a TE < 25ms.

ⁱ Advanced sequences can be substituted into this time slot, so long as 3D post-contrast T1-weighted images are collected between 4 and 8 min after contrast injection and this timing is constant across all MR exams performed in each patient.

^j 3D FLAIR is an optional alternative to 2D FLAIR, with sequence parameters as follows per EORTC guidelines: 3D TSE/FSE acquisition; TE = 90–140 ms; TR = 6000–10,000 ms; TI = 2000–2500 ms (chosen based on vendor recommendations for optimized protocol and field strength); GRAPPA≤2; Fat Suppression; Slice thickness ≤ 1.5mm; Orientation Sagittal or Axial; FOV ≤ 250 mm x 250 mm; Matrix ≥ 244x244.

^k Choice of TI should be chosen based on the magnetic field strength of the system (eg, TI ≈ 2000ms for 1.5T and TI ≈ 2500ms for 3T).

^l In order to ensure comparable SNR older 1.5T MR systems can use contiguous (no interslice gap) images with 5mm slice thickness or increase NEX for slice thickness ≤4mm.

^m For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5–15 ms for similar contrast.

ⁿ For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400–450 ms for similar contrast.

^p Older model MR scanners that are not capable of >2 b-values should use b = 0 and 1000 s/mm².

^q Axial 2D T2-weighted FLAIR and Axial 2D T2-weighted images can be interchanged pre- and post-contrast.

^r Sites may choose to perform the 3D T1w IR-GRE sequence prior to the 2D T1w TSE/SE because of the potential risk of patient movement and to help with patient comfort. However, there is less inherent lesion conspicuity in the 3D T1w IR-GRE sequence, so delaying this sequence to the end may be efficacious.

^s Acceptable 3D T1w TSE sequences include CUBE (GE), SPACE (Siemens), VISTA (Philips), isoFSE (Hitachi), or 3D MVOX (Canon)

^t Flip angles for 3D TSE sequences (including CUBE and SPACE) are complicated because many utilize variable flip angle refocusing radiofrequency pulses to produce the desired image contrast. Investigators are encouraged to work with their scanner vendors to determine the ideal parameters.

^u Investigators are encouraged to work with their scanner vendors to determine the best parallel imaging strategies, which may include simultaneous multislice imaging (SMS), controlled aliasing in parallel imaging resulting in higher acceleration (CAIPI), iPAT, GRAPPA, as well as turbo or other acceleration factors.

^v While some sites may choose to collect DWI post-contrast, studies have suggested this can lower ADC measurements as much as 3%.¹⁵²

Table 2.

Minimum standard 3T metastatic brain tumor imaging protocol

	3D T1w Preb	Ax 2D FLAIRj,q	Ax 2D DWIp,u		Ax 2D T2wh,i,q	2D SE T1w Postr,s	3D T1w Postb,r
Sequence	IR-GREd,e,f	TSEc	SS-EPIg	Contrast Injection a	TSEc	TSE/SE	IR-GRE d,e,f
Plane	Sagittal or Axial	Axial	Axial		Axial	Axial and/or Coronal	Sagittal or Axial
Mode	3D	2D	2D		2D	2D	3D
TR [ms]	2100m	>6000	>5000		>2500	< 500	2100m
TE [ms]	Min	100–140	Min		80–120	Min	Min
TI [ms]	1100n	2000–2500k					1100n
Flip angle	10º-15º	90º/≥160º	90º/180º		90º/≥160º	90º/≥160º	10º-15º
Frequency	256	≥256	128		≥256	≥256	256
Phase	256	≥256	128		≥256	≥256	256
NEX	≥1	≥1	≥1		≥1	≥1	≥1
FOV	256 mm	240 mm	240 mm		240 mm	240 mm	256 mm
Slice thickness	1 mm	3 mm	3 mm		3 mm	3 mm	1 mm
Gap/spacing	0	0	0		0	0	0
Other options			b = 0, 500, 1000 s/mm2 ≥3 directions			Fat suppression encouraged
Parallel imaging	Up to 3x t	Up to 2x	Up to 2x		Up to 2x	Up to 2x	Up to 3x t

Abbreviations: TR = repetition time; TE = echo time; TI = inversion time; NEX = number of excitations; FOV = field of view.

^a 0.1 mmol/kg dose injection with a gadolinium chelated contrast agent. Use of a power injector is desirable at an injection rate of 3–5 cc/sec. (Note: If DSC perfusion is collected, contrast injection is performed after starting DSC acquisition. DSC perfusion can be performed with the “ideal” protocol at 3T as well as with the minimum standard protocols at 3T and 1.5T.)

^b Post-contrast 3D T1-weighted images should be collected with equivalent parameters to pre-contrast 3D T1-weighted images.

^c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, Toshiba).

^d FL2D = two-dimensional fast low angle shot (FLASH; Siemens) is equivalent to the spoil gradient recalled echo (SPGR; GE) or T1- fast field echo (FFE; Philips), fast field echo (FastFE; Toshiba), or the radiofrequency spoiled steady state acquisition rewound gradient echo (RSSG; Hitachi). A fast gradient echo sequence without inversion preparation is desired.

^e IR-GRE = inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled gradient-echo (IR-SPGR or Fast SPGR with inversion activated or BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba).

^f A 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE or another IR-prepped 3D T1-weighted sequences and therefore should be avoided.

^g In the event of significant patient motion, a radial acquisition scheme may be used (eg, BLADE [Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, this acquisition scheme is can cause significant differences in ADC quantification and therefore should be used only if EPI is not an option. Further, this type of acquisition takes considerable more time.

^h Dual echo PD/T2 TSE is optional for possible quantification of tissue T2. For this sequence, PD is recommended to have a TE < 25ms.

ⁱ Advanced sequences can be substituted into this time slot, so long as 3D post-contrast T1-weighted images are collected between 4 and 8 min after contrast injection.

^j 3D FLAIR is an optional alternative to 2D FLAIR, with sequence parameters as follows per EORTC guidelines: 3D TSE/FSE acquisition; TE = 90–140 ms; TR = 6000–10,000 ms; TI = 2000–2500 ms (chosen based on vendor recommendations for optimized protocol and field strength); GRAPPA≤2; Fat Suppression; Slice thickness ≤ 1.5mm; Orientation Sagittal or Axial; FOV ≤ 250 mm x 250 mm; Matrix ≥ 244x244.

^k Choice of TI should be chosen based on the magnetic field strength of the system (eg, TI ≈ 2000ms for 1.5T and TI ≈ 2500ms for 3T).

^l In order to ensure comparable SNR older 1.5T MR systems can use contiguous (no interslice gap) images with 5mm slice thickness or increase NEX for slice thickness ≤4mm.

^m For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5–15 ms for similar contrast.

ⁿ For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400–450 ms for similar contrast.

^p Older model MR scanners that are not capable of >2 b-values should use b = 0 and 1000 s/mm².

^q Axial 2D T2-weighted FLAIR and Axial 2D T2-weighted images can be interchanged pre- and post-contrast.

^r Sites may choose to perform the 3D T1w IR-GRE sequence prior to the 2D T1w TSE/SE because of the potential risk of patient movement and to help with patient comfort. However, there is less inherent lesion conspicuity in the 3D T1w IR-GRE sequence, so delaying this sequence to the end may be efficacious.

^s Adding FLAIR to this T1-weighted imaging at 3T could be considered for CSF suppression.

^t Investigators are encouraged to work with their scanner vendors to determine the best parallel imaging strategies, which may include simultaneous multislice imaging (SMS), controlled aliasing in parallel imaging resulting in higher acceleration (CAIPI), iPAT, GRAPPA, as well as turbo or other acceleration factors.

^u While some sites may choose to collect DWI post-contrast, studies have suggested this can lower ADC measurements as much as 3%.¹⁵²

Table 3.

Minimum standard 1.5T metastatic brain tumor imaging protocol

	3D T1w Preb	Ax 2D FLAIRj,q	Ax 2D DWIp,t		Ax 2D T2wh,i,q	2D SE T1w Postr	3D T1w Postb,r
Sequence	IR-GRE d,e,f	TSEc	SS-EPIg	Contrast Injection a	TSEc	TSE/SE	IR-GRE d,e,f
Plane	Sagittal or Axial	Axial	Axial		Axial	Axial and/or Coronal	Sagittal or Axial
Mode	3D	2D	2D		2D	2D	3D
TR [ms]	2100m	>6000	>5000		>3500	400–600	2100m
TE [ms]	Min	100–140	Min		80–120	Min	Min
TI [ms]	1100n	2000–2500k					1100n
Flip angle	10º-15º	90º/≥160º	90º/180º		90º/≥160º	90º/≥160º	10º-15º
Frequency	≥172	≥256	128		≥256	≥256	≥172
Phase	≥172	≥256	128		≥256	≥256	≥172
NEX	≥1	≥1	≥1		≥1	≥1	≥1
FOV	256 mm	240 mm	240 mm		240 mm	240 mm	256 mm
Slice thickness	≤1.5 mm	≤4 mml	≤4 mml		≤4 mml	≤4 mml	≤1.5 mm
Gap/spacing	0	0	0		0	0	0
Other options			b = 0, 500, 1000 s/mm2 ≥3 directions			Fat suppression encouraged
Parallel Imaging	Up to 2xs	Up to 2x	Up to 2x		Up to 2x	Up to 2x	Up to 2xs

Abbreviations: TR = repetition time; TE = echo time; TI = inversion time; NEX = number of excitations; FOV = field of view.

^a 0.1 mmol/kg dose injection with a gadolinium chelated contrast agent. Use of a power injector is desirable at an injection rate of 3–5 cc/sec. (Note: If DSC perfusion is collected, contrast injection is performed after starting DSC acquisition)

^b Post-contrast 3D T1-weighted images should be collected with equivalent parameters to pre-contrast 3D T1-weighted images

^c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, Toshiba)

^d FL2D = two-dimensional fast low angle shot (FLASH; Siemens) is equivalent to the spoil gradient recalled echo (SPGR; GE) or T1- fast field echo (FFE; Philips), fast field echo (FastFE; Toshiba), or the radiofrequency spoiled steady state acquisition rewound gradient echo (RSSG; Hitachi). A fast gradient echo sequence without inversion preparation is desired.

^e IR-GRE = inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled gradient-echo (IR-SPGR or Fast SPGR with inversion activated or BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba).

^f A 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE or another IR-prepped 3D T1-weighted sequences and therefore should be avoided.

^g In the event of significant patient motion, a radial acquisition scheme may be used (eg, BLADE [Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, this acquisition scheme is can cause significant differences in ADC quantification and therefore should be used only if EPI is not an option. Further, this type of acquisition takes considerable more time.

^h Dual echo PD/T2 TSE is optional for possible quantification of tissue T2. For this sequence, PD is recommended to have a TE < 25ms.

ⁱ Advanced sequences can be substituted into this time slot, so long as 3D post-contrast T1-weighted images are collected between 4 and 8 min after contrast injection.

^j 3D FLAIR is an optional alternative to 2D FLAIR, with sequence parameters as follows per EORTC guidelines: 3D TSE/FSE acquisition; TE = 90–140 ms; TR = 6000–10,000 ms; TI = 2000–2500 ms (chosen based on vendor recommendations for optimized protocol and field strength); GRAPPA≤2; Fat Suppression; Slice thickness ≤ 1.5mm; Orientation Sagittal or Axial; FOV ≤ 250 mm x 250 mm; Matrix ≥ 244x244.

^k Choice of TI should be chosen based on the magnetic field strength of the system (eg, TI ≈ 2000ms for 1.5T and TI ≈ 2500ms for 3T).

^l In order to ensure comparable SNR older 1.5T MR systems can use contiguous (no interslice gap) images with 5mm slice thickness or increase NEX for slice thickness ≤4mm.

^m For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5–15 ms for similar contrast.

ⁿ For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400–450 ms for similar contrast.

^p Older model MR scanners that are not capable of >2 b-values should use b = 0 and 1000 s/mm².

^q Axial 2D T2-weighted FLAIR and Axial 2D T2-weighted images can be interchanged pre- and post-contrast.

^r Sites may choose to perform the 3D T1w IR-GRE sequence prior to the 2D T1w TSE/SE because of the potential risk of patient movement and to help with patient comfort. However, there is less inherent lesion conspicuity in the 3D T1w IR-GRE sequence, so delaying this sequence to the end may be efficacious.

^s Investigators are encouraged to work with their scanner vendors to determine the best parallel imaging strategies, which may include simultaneous multislice imaging (SMS), controlled aliasing in parallel imaging resulting in higher acceleration (CAIPI), iPAT, GRAPPA, as well as turbo or other acceleration factors.

^t While some sites may choose to collect DWI post-contrast, studies have suggested this can lower ADC measurements as much as 3%.¹⁵²

The standard protocol limits GBCA administration to a single-dose (0.1 mmol/kg) bolus, based on recent data on DSC-MRI accuracy in the primary brain tumor setting,^146,147 but we also allow for double, 0.2 mmol/kg total GBCA dosing if investigators and sites prefer. If a double dose of GBCA is used and DSC perfusion is performed, the first GBCA dose should be used as gadolinium preload, preceding the DSC series, which would then use the second GBCA dose. A higher relaxivity GBCA, for greater lesion contrast conspicuity and possibly improved DSC signal change (especially at 1.5T), is preferable but not mandated.

If sites have 3T scanners and if patients have no contraindications to scanning at 3T, we recommend acquiring brain imaging at 3T over 1.5T, as the advantages at 3T outweigh disadvantages. The current literature suggests that the most sensitive pulse sequence for the detection of small metastases is 3D TSE T1-weighted imaging with greater sensitivity at 3T compared with 1.5T. Three-dimensional TSE T1-weighted imaging at 1.5T has not been well evaluated for brain metastasis detection, and its quality can vary depending upon scanner platform. Therefore, we recommend 3D TSE T1-weighted imaging be used at 3T but cannot universally endorse it at 1.5T until additional studies are conducted.

For sites not able to perform stand-alone 3D TSE T1-weighted imaging and would use the “standard” protocol with 3D IR-GRE instead, we recommend the addition of one post-contrast 2D SE or TSE T1-weighted series at the conclusion of the MR exam both for clinical purposes and for trial outcome purposes. This can assist in the detection of small metastases that may not be detected on IR-GRE imaging or which may be obscured by artifacts that differ between the 2 post-contrast pulse sequences. For instance, a second post-contrast T1-weighted series may increase diagnostic confidence when considering SRS to new very small metastases, or if artifacts are present in a particular location on one imaging series. Although we advocate for acquisition of this additional sequence, we are not providing specific parameters for the second post-contrast T1-weighted series because: (i) we encourage sites to perform their best possible pulse sequence, which may vary significantly, and (ii) for clinical trial evaluation purposes and generalizability, the 3D post-contrast T1-weighted scan should be used for measurements and advanced image post-processing, whereas the post-contrast SE or TSE series can be used in a qualitative way to support the accuracy of the BTIP-based protocol. We recommend that such a 2D SE/TSE T1-weighted series have slice thickness no greater than 4 mm and no interslice gap.

Acknowledging that some imaging sites may routinely perform either turbo spin echo T2-weighted or T2-weighted FLAIR imaging in order to reduce exam time, we recommend acquiring both. Current automated segmentation algorithms utilize both T2- and T2-weighted FLAIR, which may be important for some trials. However, if sites are able to acquire only one of these sequences, primary investigators could consider this as acceptable, although less optimal. For instance, primarily cystic metastases may be best appreciated on T2-weighted imaging.

As T2-weighted FLAIR is also performed pre-GBCA administration at some sites, and post-GBCA administration at others, we also allow for investigators and/or sites to choose this timing of T2-weighted FLAIR, simply pointing out that post-contrast T2-weighted FLAIR will depict as bright not only lesions with T2 lengthening but also GBCA-enhancing lesions. Advantages of performing T2-weighted FLAIR post-gadolinium include the potentially better conspicuity of leptomeningeal metastases and some parenchymal metastases. Lastly, it is crucial that at least one pulse sequence be performed between the administration of GBCA and the first post-contrast T1-weighted series, to optimize lesion contrast enhancement. Typically, T2-weighted imaging is performed as this temporal “spacer,” since GBCA enhancement is not detectable in non-FLAIR T2-weighted images. However, if sites do not perform routine T2-weighted imaging, they will need another pulse sequence such as a T2-weighted FLAIR at this time point in the imaging protocol.

Some imaging centers routinely perform susceptibility weighted imaging (SWI), which has very good sensitivity for paramagnetic substances such as hemosiderin in hemorrhagic tumors and deoxyhemoglobin in veins. SWI indicates the presence of hemorrhage in many metastases,⁵⁴ which may have some utility in their evaluation, though SWI alone is not as sensitive for small metastases as is post-contrast T1-weighted imaging. Investigators should feel free to include SWI or allow it if desired; its only downside is that it requires MR gradient time on the order of 5 minutes.

It is strongly encouraged that imaging centers employ the same MRI scanner platform, including field strength, and the same imaging protocol, at all scan time points for any given patient. This will aid in accurately evaluating imaging changes over time. A cautionary note for clinical investigators is warranted here. The clear advantages to the “ideal” protocol over the “minimum standard” protocol justify its being used whenever possible, and its inclusion in this document could serve to also better inform sites when they are upgrading their MRI equipment. However, because many sites will not be able to perform the “ideal” protocol or may have only a single or limited number of capable scanners, this could present a challenge to performing follow-up MR exams on a given patient on the same scanner platform. This underscores the need for clear communication and cooperation with radiology departments or imaging centers.

The aforementioned protocol is meant to provide a fundamental standard for use in clinical trials involving brain metastases. Sites are welcome to add additional pulse sequences to meet their particular clinical needs. For example, some sites may feel more comfortable always acquiring a second, confirmatory post-contrast T1-weighted sequence for greater certainty in identifying small metastases, particularly if there are artifacts. Also, sites may consider adding other imaging techniques with which they have experience and skill, such as 1-hour delayed post-contrast T1-weighted imaging, ASL, DCE, MR spectroscopy, or PET for better differentiation of radiation necrosis and recurrent tumor in the post-SRS setting.

Conclusion

Brain metastases present some unique imaging challenges compared with gliomas. We therefore provide suggestions for a “minimum standard” as well as “ideal” MR imaging protocols, depending on imaging sites’ capabilities, that should serve well for clinical purposes as well as for patients with brain metastases on clinical trials.

Funding

None.

Conflict of interest statement

Patrick Wen: research support: Agios, Astra Zeneca/Medimmune, Beigene, Celgene, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Vascular Biogenics, VBI Vaccines. Priscilla Brastianos: research funding: Merck, BMS, Lilly, Pfizer. Raymond Huang: research support: Agios Pharmaceuticals (not relevant to topic). Michael Weller: research grants from Abbvie, Adastra, Bristol-Myers Squibb (BMS), Dracen, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Piqur, and Roche. Eva Galanis: research funding: MedImmune, Inc, Denovo Biopharma, Tracon, Genentech, Bristol-Myers Squibb. Caroline Chung: research funding: Siemens. Nancy Lin: research funding: Merck, Pfizer, Genentech, Seattle Genetics.

Advisory affiliations. Patrick Wen: Agios, Astra Zeneca, Bayer, Blue Earth Diagnostics, Immunomic Therapeutics, Karyopharm, Kiyatec, Puma, Taiho, Vascular Biogenics, Deciphera, VBI Vaccines, Tocagen, Voyager. Priscilla Brastianos: Tesaro, Angiochem, Lilly, Genentech-Roche. Dan Barboriak: Blue Earth Diagnostics; GE Neuro MRI (no reimbursement). Terry Burns: Neurametrix.

Management affiliations: Marion Smits: On national guideline committee for Brain Metastasis in the Netherlands.

Paid consulting: Patrick Wen: Merck, Prime Oncology. Priscilla Brastianos: Genentech-Roche, Merck, ElevateBio. Eva Galanis: General Consulting: MedImmune, Inc; F. Hoffman La Roche, Ltd (compensation to Mayo) Tactical Therapeutics, Inc; Oncorus (personal compensation); and Advisory Board: Vyriad (compensation to Mayo). Celgene Corporation; KIYATEC (personal compensation). Paul Brown: UpToDate contributor (personal compensation). Marion Smits: GE Healthcare (speaker fees). Michael Weller: Honoraria for lectures or advisory board participation or consulting from Abbvie, Basilea, Bristol-Myers Squibb (BMS), Celgene, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Orbus, Roche, and Tocagen. Nancy Lin: Consulting/advisory board: Seattle Genetics, Daiichi Sankyo.