iRANO criteria

The immunotherapy response assessment for neuro-oncology (iRANO) criteria have been developed as a modification of RANO criteria to address the challenges of emerging novel immunotherapy for high-grade gliomas ¹. Although these criteria have been primarily for the purposes of standardizing assessment of treatment response in the setting of clinical trials, they offer important guiding principles for everyday reporting. 

A form of pseudoprogression is encountered in immunotherapy that is distinct to that seen in routine chemo-radiotherapy (Stupp protocol) both in mechanism and imaging appearances. Furthermore, unlike chemoradiotherapy, the onset of treatment effect in immunotherapy may be somewhat delayed ¹. 

Unlike antiangiogenesis agents (e.g. bevacizumab), immunotherapy does not result in pseudoresponse ¹. 

Key differences between iRANO and RANO criteria

• new enhancing lesion outside the main radiation field are encountered in immunotherapy and therefore do not automatically denote progressive disease in iRANO

• the onset of therapeutic effect in immunotherapy can be delayed and thus iRANO requires a repeat scan (3 months later) to confirm disease progression on imaging criteria (see below)

Progressive disease

Progressive disease can be diagnosed in the setting of immunotherapy in the following scenarios ¹:

• clinical features

  • significant clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease)

• imaging features

  • >6 months of the current immunotherapeutic regimen

    • same as RANO progressive disease criteria

  • ≤6 months of the current immunotherapeutic regimen

    • requires a second scan confirming further progressive disease 3 months after the initial scan showing features of progressive disease

    • during this interval, immunotherapy can continue if toxicity is minimal, at the discretion of treating clinicians

Role of histopathology

It should be noted that although histology has always been considered the "gold standard" in determining true tumor progression from pseudoprogression, in the setting of immunotherapy this distinction can be challenging. Small biopsy samples are prone to sampling bias and will often show mixed tissue components with both tumor and inflammatory cells being present ¹.