Immunotherapy response assessment in neuro-oncology: a report of the RANO working group

Abstract

Immunotherapy represents a promising area of therapy among neuro-oncology patients. However, early phase studies reveal unique challenges associated with assessment of radiological changes reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumor regression, can still occur following initial apparent progression or appearance of new lesions. Refinement of response assessment criteria for neuro-oncology patients undergoing immunotherapy is therefore warranted. A multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describes immunotherapy response assessment for neuro-oncology (iRANO) criteria that are based on guidance for determination of tumor progression outlined by the immune-related response criteria (irRC) and the response assessment in neuro-oncology (RANO) working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease (PD) within six months of initiating immunotherapy including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for use of corticosteroids. The role of advanced imaging techniques and measurement of clinical benefit endpoints including neurologic and immunologic functions are reviewed. The iRANO guidelines put forth herein will evolve successively to improve their utility as further experience from immunotherapy trials in neuro-oncology accumulate.

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape

“…Activation of the immune response during immunotherapy may directly or indirectly result in increased BBB leakiness, resulting in increased contrast enhancement mimicking tumor progression. Specifically, immunotherapies can cause leukocyte infiltration at sites of active tumor resulting in disruption of the BBB and increased contrast enhancement [56,57]. The specific changes or patterns in conventional MRI following immunotherapy, however, are not well characterized due to the limited experience and small study sizes to date.…”

“…Because of the significant risk of mistakenly interpreting pseudoprogression for tumor progression, which would terminate use of a potentially beneficial therapy by taking patients off study early, investigators have proposed guidelines for assessing malignant patients treated with immunotherapy called the "immunotherapy response assessment for neurooncology" (iRANO) criteria [57]. The main difference from RANO is that iRANO advocates for additional confirmation scans if patients demonstrate PD within the first 6 months of initiating therapy and are neurologically stable.…”

Perspectives for immunotherapy in endocrine cancer

“…In 2009 immune-related response criteria were first proposed for ipilimumab therapy in malignant melanoma patients (Wolchok et al 2009) and were subsequently evaluated also for pembrolizumab treatment (Hodi et al 2016). This issue has also been discussed in neurooncology (Okada et al 2015) and for non-small cell lung cancer (Socinski 2015). A comprehensive overview of the application and relevance of immune-related response criteria is given by Hoos et al (2015).…”

Current State of Immune-Based Therapies for Glioblastoma

“…24,25 As a result, many trials have built in lag times for imaging to allow patients to continue therapy and to avoid considering the treatment a failure. In glioblastoma, Okada et al 26 have developed an iRANO protocol specifically tailored for immunotherapy.…”