Elsevier

The Lancet Oncology

Volume 16, Issue 6, June 2015, Pages e270-e278
The Lancet Oncology

Review
Response assessment criteria for brain metastases: proposal from the RANO group

https://doi.org/10.1016/S1470-2045(15)70057-4Get rights and content

Summary

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. 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, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. 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.

Introduction

Brain metastases are the most common cause of malignant brain tumours in adults. Of the nearly 1·5 million patients in the USA who received a primary diagnosis of cancer in 2007, about 70 000 of these primary diagnoses are estimated to eventually relapse in the brain.1, 2 Despite the frequency of brain metastases, prospective trials in this patient population are limited, and the criteria used to assess response and progression in the CNS are heterogeneous.3 This heterogeneity largely stems from the recognition that existing criteria sets, such as RECIST,4, 5 WHO,6 or Macdonald Criteria,7 are themselves distinct and have gaps and limitations in their ability to address issues specific to the assessment of patients with brain metastases (table 1).5 Key issues in the imaging of CNS metastases include the modality and frequency of assessment, the method of measurement (linear, bidimensional, volumetric), the magnitude of change that defines response or progression, differentiation between tumour-related and treatment-related changes, the inclusion (or exclusion) of corticosteroid use and clinical signs and symptoms with imaging definitions of progression and response, and the inclusion (or exclusion) of systemic disease status into the definition of CNS response and progression.

Section snippets

Scope and purpose of the proposed RANO-BM criteria

Prospective clinical trials to assess new treatments for patients with active brain metastases are becoming increasingly common. Additionally, we welcome the trend away from automatic exclusion of patients with brain metastases from clinical trials of novel therapies. The concurrent proliferation of response criteria for assessment of CNS metastases has made interpretation of trial results challenging. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group first

Process of RANO-BM criteria development

The RANO-BM is an international group of experts in medical oncology, neuro-oncology, radiation oncology, neurosurgery, neuroradiology, neuropsychology, biostatistics, and drug development who, in collaboration with government and industry partners, are working towards the development of more streamlined and broadly acceptable criteria for assessment of brain metastases. After completion of a literature review and critique, the group convened a series of meetings and regular teleconferences to

Proposed RANO-BM criteria

Similar to RECIST 1.1, definitions for radiographical response will be based on unidimensional measurements.

Definition of best overall CNS response

Best overall CNS response is a composite of radiographical CNS target and non-target lesion responses (panel 1), corticosteroid use, and clinical status. For non-randomised trials in which CNS response is the primary endpoint, confirmation of partial response or complete response at least 4 weeks later is necessary to deem either one the best overall response.

At each protocol-specified timepoint, a response assessment should occur and CNS assessments should be coincident with extra-CNS

Volumetric criteria

Research of the value of volumetric versus unidimensional measurements for the assessment of CNS lesion response is ongoing.15, 16, 17, 18 Volumetric measurement was the topic of much discussion and debate within the RANO-BM group. The RANO-BM group judges that the existing data are not yet strong enough to justify the universal requirement of volumetric response criteria in clinical trials of patients with brain metastases. Volumetric analyses in real-time adds cost and complexity and is not

Treatment of non-CNS (extracranial) disease

Preclinical and clinical data sometimes show a differential response in intracranial versus extracranial locations, which could be related to inadequate drug penetration, differences in tumour microenvironment, or tumour heterogeneity between organ sites, among other possibilities. Many systemic agents are not expected to have CNS activity, primarily because of poor drug penetration. Local CNS therapies, such as whole-brain radiotherapy, stereotactic radiosurgery, or surgery, are not expected

Additional endpoints for localised therapy trials

Patients with brain metastases frequently undergo focal treatments such as surgical resection and stereotactic radiosurgery. With these modalities, the technical success of the treatment is appropriately measured by assessment of the site of localised therapy and not distant sites. For example, outcomes after stereotactic radiosurgery are commonly reported as local control (ie, control of the treated lesion) and distant brain failure (ie, the appearance of new or progressive lesions outside the

Conclusion

We recognise that our proposal adds complexity to the assessment of patients with brain metastases enrolled in clinical trials. However, limitations of the existing response criteria have led to frequent, but inconsistent, modifications by investigators. Additionally, because brain metastases can be treated using multiple modalities, which might or might not have effects outside of the treated field or outside the brain, endpoints in trials have also been defined differently according to the

Search strategy and selection criteria

We searched Medline, PubMed, and the references of relevant articles using the following search terms: “brain metastases”, “breast cancer”, “lung cancer”, “melanoma”, “whole brain radiotherapy”, “stereotactic radiosurgery”, and “radiation necrosis”. Additional cross-referenced search terms were added for specific topics such as “volumetric”, “perfusion MRI”, “positron emission tomography”, and “immunotherapy”. We included only articles published in English between Jan 1, 1980, and Oct 1, 2014.

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