In order to compare responses to different therapies among clinical trials and to differentiate between therapy-induced changes and true tumor progression, reliable response parameters are crucial.
MRI scans were evaluated using MacDonald, RANO, Vol-RANO, mRANO, Vol-mRANO and iRANO criteria. Tumor volumes (T1 contrast-enhancing as well as T2/FLAIR volumes) were calculated by semiautomatic segmentation.
Glioblastoma (GB) is the most frequent primary brain tumor in adults [1,2]
. Despite multimodal treatment, life expectancy is still poor [3,4,5]
. Considering the enormous progress in cancer immunotherapy during the past few years, a number of new immunologic treatment approaches, including personalized cell vaccines, are currently under investigation for GB. Unfortunately, no significant improvement in overall survival (OS) or progression-free survival (PFS) has been observed so far [6,7,8,9,10,11,12,13,14]
. To compare the treatment responses between different therapies among clinical trials and to differentiate between therapy-induced changes and true tumor progression, reliable response parameters are crucial. Magnetic resonance imaging (MRI) is the gold standard for evaluating response and progression during treatment. However, different treatments, in particular radiotherapy combined with temozolomide chemotherapy as well as immunologic strategies, challenge the current imaging response criteria. Pseudoprogression (PsP), a subacute treatment-related phenomenon, results from a disruption of the blood–brain barrier and presents an increased contrast enhancement on MRI, mimicking tumor progression 
. PsP was reported in up to 10–30% of GB patients following radiochemotherapy [16,17]
. Other than that, patients treated with antiangiogenic therapies often show a decrease in contrast enhancement but without a true tumor response, also referred to as a pseudoresponse (PrP). Frequently, progression is only observable as a non-enhancing abnormality in T2-weighted or fluid-attenuated inversion recovery (FLAIR) image sequences in those patients 
In recent years, several radiologic assessment tools have been proposed 
. In 1990 the MacDonald criteria were introduced, using two-dimensional tumor measurements, as well as corticosteroid use and the clinical performance of the patient for response assessment 
. Twenty years later, the Response Assessment in Neuro-Oncology (RANO) criteria were proposed 
, utilizing T2-weighted or FLAIR image sequences to account for non-enhancing tumor components and therapy-induced MRI changes such as PsP and PrP [21,22]
. To better account for the phenomenon of PsP, the modified RANO (mRANO) criteria were proposed in 2017, which require a confirmation scan to better capture the occurrence of true tumor progression or PsP in GB patients 
. With the advent of immunotherapies, unique patterns of responses were observed during the treatment of systemic cancer. Especially within the first weeks after starting immunotherapy the appearance of new local or distant lesions or an increase in existing lesions may simply reflect an immune-mediated phenomenon rather than true tumor progression 
. In consideration of such PsP during immunotherapy of GB, the Immunotherapy RANO (iRANO) criteria 
were developed. Interestingly, the iRANO criteria were developed before the true incidence of PsP during immunotherapy was established, which in consecutive studies was found to range between 10–15% [26,27]
. So far, only a few studies [28,29]
exist, which directly compare and evaluate currently available response criteria.
2. Progression-Free Survival and Postprogression Survival
All patients had undergone gross total tumor resection. No measurable tumor mass was detected on postsurgery MRI, so the best possible response for every patient was SD.
PFS differed significantly between the individual response-assessment criteria. Overall, there was a significant difference in median PFS between mRANO (8.6 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.0 months), RANO (4.2 months) and Vol-RANO (5.4 months). In the Audencel subgroup, there was a significant difference in median PFS between mRANO (8.1 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.2 months). In Table 13
, the specific p
-values and median PFS with CI for all assessment criteria are listed. Interestingly, there was no difference in PFS between SOC and SOC + Audencel using the different response-assessment criteria.
Table 13. Median progression-free survival with the corresponding confidence interval for the different assessment criteria. Calculated p-values (Kruskal–Wallis test) and corrected for multiple testing (Bonferroni’s adjustment) for difference in PFS between assessment criteria.
|Median PFS, Months
||Difference of PFS (p-Value)
|Median PPS, Months
||Difference of PPS (||p-Value)