Response Assessment in NeuroOncology Brain Metastases working group [Neurosurgery Wiki]

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====== Response Assessment in NeuroOncology Brain Metastases working group ======

The Response Assessment in [[NeuroOncology]] [[Brain Metastases]] (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in [[clinical trial]]s of treatment for brain metastases. 

The group convened in 2011 to review the medical literature and propose new standard criteria for the radiological assessment of brain metastases in clinical trials
((NU Lin, JS Wefel, EQ Lee, et al. Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group Lancet Oncol, 14 (2013), pp. e407–e416)).

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The group provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. They also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. They consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. They also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials
((Camidge DR, Lee EQ, Lin NU, Margolin K, Ahluwalia MS, Bendszus M, Chang SM,
Dancey J, de Vries EGE, Harris GJ, Hodi FS, Lassman AB, Macdonald DR, Peereboom
DM, Schiff D, Soffietti R, van den Bent MJ, Wefel JS, Wen PY. Clinical trial
design for systemic agents in patients with brain metastases from solid tumours: 
a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working
group. Lancet Oncol. 2018 Jan;19(1):e20-e32. doi: 10.1016/S1470-2045(17)30693-9. 
Review. PubMed PMID: 29304358.
)).
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The goals of therapeutic and biomarker development form the foundation of clinical trial design, and change considerably from early-phase to late-phase trials. From these goals, decisions on specific clinical trial design elements, such as endpoint selection and statistical approaches, are formed. Whereas early-phase trials might focus on finding a therapeutic signal to make decisions on further development, late-phase trials focus on the confirmation of therapeutic impact by considering clinically meaningful endpoints. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we highlight issues related to, and provide recommendations for, the design of clinical trials on local therapies for CNS metastases from solid tumours. We discuss endpoint selection criteria, the analysis appropriate for early-phase and late-phase trials, the association between tumour-specific and clinically meaningful endpoints, and possible issues related to the estimation of local control in the context of competing risks. In light of these discussions, we make specific recommendations on the clinical trial design of local therapies for brain metastases
((Alexander BM, Brown PD, Ahluwalia MS, Aoyama H, Baumert BG, Chang SM, Gaspar
LE, Kalkanis SN, Macdonald DR, Mehta MP, Soffietti R, Suh JH, van den Bent MJ,
Vogelbaum MA, Wefel JS, Lee EQ, Wen PY; Response Assessment in Neuro-Oncology
(RANO) group. Clinical trial design for local therapies for brain metastases: a
guideline by the Response Assessment in Neuro-Oncology Brain Metastases working
group. Lancet Oncol. 2018 Jan;19(1):e33-e42. doi: 10.1016/S1470-2045(17)30692-7. 
Review. PubMed PMID: 29304360.
)).
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Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neurocognitive, and quality-of-life endpoints into trials of patients with brain metastases. 

The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials
((Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, Bendszus M,
Brown PD, Camidge DR, Chang SM, Dancey J, de Vries EG, Gaspar LE, Harris GJ, Hodi
FS, Kalkanis SN, Linskey ME, Macdonald DR, Margolin K, Mehta MP, Schiff D,
Soffietti R, Suh JH, van den Bent MJ, Vogelbaum MA, Wen PY; Response Assessment
in Neuro-Oncology (RANO) group. Response assessment criteria for brain
metastases: proposal from the RANO group. Lancet Oncol. 2015 Jun;16(6):e270-8.
doi: 10.1016/S1470-2045(15)70057-4. Epub 2015 May 27. Review. PubMed PMID:
26065612.
)).

====Definitions====

===Measurable disease=== 

Defined as a contrast-enhancing lesion that can be accurately measured in at least one dimension, with a minimum size of 10 mm, and is visible on two or more axial slices that are preferably 5 mm or less apart with 0 mm skip (and ideally ≥1·5 mm apart with 0 mm skip). Additionally, although the longest diameter in the plane of measurement is to be recorded, the diameter perpendicular to the longest diameter in the plane of measurement should be at least 5 mm for the lesion to be considered measurable. If the MRI is performed with thicker slices, the size of the measurable lesion at baseline should be at least double the slice thickness. Interslice gaps, if present, should also be considered in the determination of the minimum size of measurable lesions at baseline. Measurement of a tumour around a cyst or surgical cavity is a particularly difficult challenge. Generally, such lesions should be considered non-measurable unless there is a nodular component that measures 10 mm or more in longest diameter and 5 mm or more in the perpendicular plane. The cystic or surgical cavity should not be measured for the determination of a response.

====Progression====
Except in the case of immunotherapy-based treatments, a new lesion is defined by any enhancing lesion that was not present on prior imaging (performed with same technique) and that is now visible on axial, coronal, and sagittal reconstructions of ≤ 1.5 mm projections (when MRI is performed with ≤ 1.5 mm slice thickness). If there is any doubt, then treatment may continue until the next scheduled assessment. If the lesion has grown, then this would confirm progression and the date of progression will be backdated to when the lesion first appeared on imaging.