NANO, a practical scale for neurologic assessments in patients with brain tumors?

See article in this issue by Nayak et al. pp. 625–635. The development of new therapies for patients with brain tumors has been a challenging and arduous process. In recent years, several promising agents for glioblastoma have furnished disappointing results when tested in large phase III trials despite promising initial signals of efficacy.1,2 Have shortcomings in the rating scales used by neuro-oncologists played a role in these failures and hindered therapeutic advancements in the field? To address this question, the Response Assessment in Neuro-Oncology (RANO) Working Group was formed a few years ago. This international and multidisciplinary expert panel was convened for the express purpose of developing new standardized response criteria for use in clinical trials involving patients with brain tumors. To date, the most significant contribution of the RANO Working Group has been the publication of a formal update of the Macdonald criteria, a scale designed largely for determining radiographic response using CT imaging supplemented by clinical status and corticosteroid use.3 The updated RANO criteria were formulated to standardize the interpretation of MR images, recognizing the need to account for radiographic changes that can occur shortly after the completion of radiotherapy (“pseudoprogression”) and after exposure to anti-angiogenic agents (“pseudoresponse”).4 RANO criteria were quickly validated against RECIST (Response Evaluation Criteria In Solid Tumors) and the Macdonald criteria and incorporated into clinical trial design, not surprisingly in part because they represented minor albeit significant modifications of a scale with which the neuro-oncology community was very familiar and comfortable.5 RANO criteria represent an important milestone in the standardization of response in neuro-oncology, and if they had been used in the initial evaluation of bevacizumab and to inform design of subsequent phase III trials of this agent, perhaps a different outcome for this drug would have been observed.6 Like the Macdonald criteria, RANO criteria incorporate clinical status in determining response and progression; however, the updated criteria did not fully address how to measure a change in clinical and neurologic status, providing at best vague guidelines about what degree of change in KPS or Eastern Cooperative Oncology Group (ECOG) status would represent a meaningful clinical change. In this issue of Neuro-Oncology, members of the RANO Working Group propose a brief standardized neurologic assessment in neuro-oncology scale (NANO Scale) that can be used as a clinical tool to provide a reliable and clinically meaningful assessment of neurologic status in brain tumor patients, particularly if enrolled in clinical trials that use RANO criteria.7 The scale is simple and straightforward and designed for use by a wide range of physicians and allied health practitioners involved in the care of patients with brain tumors. The scale is not expected to replace a detailed neurologic examination as conducted by a neurologist, rather it is an efficient way to determine significant and presumably clinically relevant changes in specific neurologic functions frequently affected in patients with brain tumors. Disease-specific clinical rating scales are in widespread use for a variety of neurologic disorders such as stroke, Parkinson disease, and multiple sclerosis, and they have been incorporated not only as measures of primary and secondary outcomes in clinical trials but also as tools to aid decision making in patient care.8 Patients with brain tumors are a similarly unique population deserving of a reliable and validated tool for measuring accurately their neurologic deficits and symptom burden. The content of the NANO Scale consists of 9 neurologic domains routinely assessed and considered disease specific and most informative for patients with brain tumors. These domains are: gait, strength, upper extremity ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior. Each domain has 3 or 4 levels of functional capacity, and a prespecified change in affected domains guides the determination of response, stability, or progression. Within a domain, each level of function represents a significant and nonoverlapping change in ability that can easily be assessed reliably. Indeed, the RANO Working Group has evaluated the inter-observer agreement of this scale and, with notable and not surprising exceptions, such as the assessment of behavior, found fair to moderate agreement for most domains. Intra-observer reliability was not determined but, given the simplicity of the scale, is expected to be very high. An important feature of the NANO Scale is the process by which a change in neurologic status is determined. Unlike most multidomain scales, the assessment of response in the NANO Scale hinges on a significant change of function in a single domain and not on a composite score of all 9 domains. This is likely a reasonable approach as patients with brain tumors usually have discrete lesions that typically affect a specific neurologic function preferentially. Clinical improvement or worsening is likely to be reflected by a change in the severity of a preexisting neurologic deficit, with other areas of neurologic function largely spared or minimally affected. The NANO Scale is presently under evaluation as an exploratory endpoint in a number of clinical trials. Based on these preliminary experiences and because the content of the scale was validated by the consensus of an expert panel only, a reassessment of the relative values of the 9 domains, their predetermined levels of function, and the scoring methodology employed to determine response might be required at some future point. Standardization of response assessment has its greatest application in improving the rigor with which clinical trials are conducted, and consequently the pharmaceutical industry and regulatory agencies are keenly aware of the activities of the RANO Working Group. However, unlike the RANO criteria, which were rapidly adopted and incorporated into virtually all clinical trials in neuro-oncology shortly after their publication, the NANO Scale must be subjected to a rigorous validation process before its incorporation into clinical trials, where its use as a secondary endpoint is likely. The NANO Scale is a new tool and it is unproven. Its validation includes not only its content but also whether the scale accurately estimates the clinical condition of a patient, captures the essence of a more detailed neurologic examination, and most importantly, detects over time clinically significant changes in neurologic function that would not be discerned by more standard and validated but less neuro-oncology–specific clinical tools such as the KPS and ECOG scale. While the NANO Scale was designed to detect large changes in neurologic function, for it to be a useful clinical scale it must be sufficiently sensitive to reflect appropriately what are deemed clinically significant radiographic changes in tumor size. The NANO Scale is apparently easy to learn and can be executed in just a few minutes, but if the information it provides does not improve the accuracy of our clinical decisions, it is a tool that is ultimately redundant and therefore should not replace the more familiar clinical response assessment tools already in use. It is unlikely that the NANO Scale will become a tool that is used in the routine management of patients with brain tumors; a more detailed and conventional neurologic examination is more informative and will remain an integral component of the accepted standard of care for this population. However, the NANO Scale complements validated neurocognitive and patient-reported symptom burden scales, thereby enhancing the standardized clinical evaluation of patients with brain tumors. Finally, the NANO Scale was designed primarily to assist decision making using the RANO criteria, and here it has its greatest potential role, particularly when imaging changes are ambiguous or when clinical deterioration occurs in the absence of radiographic changes. Ultimately, reliable and valid rating scales will improve the quality of our clinical trials, accelerate therapeutic advances, and enhance the standard of patient care in neuro-oncology. The NANO Scale has the potential to aid the realization of these goals.

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