## 3 Imaging Evaluation of Therapy Response in Metastatic RCC
### Immune Checkpoint Inhibitors  
As mentioned above, ICIs act through a novel immune-mediated mechanism with T-cell-activation. These drugs are cytostatic agents which induce a delayed and slow response compared with chemotherapy; thus, atypical response patterns can be observed. One of these is called pseudo-progression, which consists of a decrease in the total tumor burden after an initial increase or the appearance of new lesions [13]. In this regard, two possible explanations have been hypothesized, such as infiltration of T cells into tumor lesions or persisted tumor growth waiting an efficient immune response [29]. Of note, pseudo-progression may be misclassified as progressive tumor disease and should be taken into account in the response assessment of metastatic RCC patients in treatment with ICIs. However, it has to be highlighted that its incidence is low and more frequent in younger patients, and true progression is more likely than pseudo-progression when an increase of tumor burden is noticed [13]. Furthermore, it is to be underlined that the response duration is shorter in such patients than those with PR or CR, although they show better outcomes than patients with typical PD [30]. Another possible tumor response is the hyperprogression, consisting of extreme acceleration of tumor growth kinetics (\(\geq\)2-fold increase of tumor growth rate before and after therapy), more frequent with anti-PD1/PD-L1 agents [31]. The underlying mechanism of this type of response has not been elucidated yet, but a significant correlation with patients' age and decreased overall survival was found [32]. Finally, ICIs can induce a dissociated tumor response characterized by the increase in size of some lesions and the decrease in size of others; the pathophysiologic explanation of this phenomenon remains unknown, thus requiring a simultaneous evaluation of tumor burden and clinical data [29]. Although relatively uncommon, radiologists have to know these atypical response patterns of ICIs therapy so that treatment is not interrupted when new lesions appear or existing lesions increase in size until progressive disease is not confirmed on a second  
Figure 1: CT axial scans in a male patient, 59 years old, with chest and abdominal lymph node metastases before (**A,C**) and after (**B,D**) medical treatment. The patient underwent left nephrectomy for the primary tumor (clear cell RCC) and was medically treated with cabozantinib (60 mg/die) when disease recurrence occurred during the post-surgical follow-up. CT images show chest (**A,B**) and abdominal para-aortic (**C,D**) partially necrotic lymphoadenopathies which remained stable at re-evaluation as stable disease according to mCHOI criteria (Table 1). follow-up scan. These atypical responses influence the clinical practice and new imaging response criteria should be considered, which include two fundamental concepts such as that a new lesion does not preclude PD and/or a confirmation of PD. In the last years different immune-adapted criteria have been suggested consisting of immune-related response criteria (irRC), immune-related RECIST (irRECIST) and immune-RECIST (iRECIST) (Table 2) [17; 29; 33; 34]. In detail, irRC were the first immune-adapted criteria and the two major innovations were the following: new measurable lesions were included into the total tumor burden and the imaging evaluation after at least 4 weeks from the previous exam is necessary to define complete response (CR), partial response (PR) and progressive disease (PD). The irRECIST differed from irRC because the measurement of tumor burden was unidimensional and not bi-dimensional, improving reproducibility. The iRECIST introduced the novel concept of immune-unconfirmed PD (iUPD) which inspires the RECIST 1.1 PD and requires confirmation by imaging re-evaluation at 4-8 weeks, defining the immune-confirmed PD (iCPD) [34]. It could be assigned two times so long as iCPD criteria has not been met; during this time interval, therapy should continue, unless a clinical worsening occurs.