Critical features and challenges associated with imaging in patients undergoing cancer immunotherapy

Critical features and challenges associated with imaging in patients undergoing cancer immunotherapy

Critical Reviews in Oncology / Hematology 120 (2017) 13–21 Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journ...

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Critical Reviews in Oncology / Hematology 120 (2017) 13–21

Contents lists available at ScienceDirect

Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc

Review article

Critical features and challenges associated with imaging in patients undergoing cancer immunotherapy

T



Cinzia Solinasa,1, Michele Porcub, ,1, Zuzana Hlavatac, Pushpamali De Silvaa, Marco Puzzonid, Karen Willard-Galloa, Mario Scartozzid, Luca Sabab a

Molecular Immunology Unit, Institut Jules Bordet and Université Libre de Bruxelles, Boulevard de Waterloo, n. 127, Brussels, Belgium Department of Radiology, Azienda Ospedaliero Universitaria of Cagliari, SS 554 Monserrato, CA, Italy c Department of Medical Oncology, CHR Mons – Hainaut, Avenue Baudouin de Constantinople, n. 5, Mons, Hainaut, Belgium d Department of Medical Oncology, Azienda Ospedaliero Universitaria of Cagliari, SS 554 Monserrato, CA, Italy b

A R T I C L E I N F O

A B S T R A C T

Keywords: Pseudoprogression Immune related response criteria Imaging Immunotherapy

Manipulating an individual’s immune system through immune checkpoint blockade is revolutionizing the paradigms of cancer treatment. Peculiar patterns and kinetics of response have been observed with these new drugs, rendering the assessment of tumor burden particularly challenging in cancer immunotherapy. The mechanisms of action for immune checkpoint blockade, based upon engagement of the adaptive immune system, can generate unusual response patterns, including pseudoprogression, hyperprogression, atypical and delayed responses. In patients treated with immune checkpoint blockade and radiotherapy, a reduction in tumor burden at metastatic sites distant from the irradiation field (abscopal effect) has been observed, with synergistic systemic immune effects provoked by this combination. New toxicities have also been observed, due to excessive immune activity in several organs, including lung, colon, liver and endocrine glands. Efforts to standardize assessment of cancer immunotherapy responses include novel consensus guidelines derived by modifying World Health Organization (WHO) and Response Evaluation Criteria In Solid Tumors (RECIST) criteria. The aim of this review is to evaluate imaging techniques currently used routinely in the clinic and those being used as investigational tools in immunotherapy clinical trials.

1. Introduction Harnessing the immune system with the goal of destroying tumor cells represents a novel and promising therapeutic strategy in medical oncology. Immunotherapy by immune checkpoint blockade (ICB) acts by preventing inhibitory interactions between immune checkpoint molecules expressed on T cells and their ligands expressed on tumor, stromal and/or immune cells in the microenvironment. The activity of ICB has been correlated with stimulation of a pre-existing anti-tumor immune response via activation of a cytotoxic effect at the tumor site, which has been observed in patients treated with anti-cytotoxic Tlymphocyte associated antigen-4 (CTLA-4) and anti-programmed death1 (PD-1) antibodies (Hodi et al., 2008; Ribas et al., 2009a; Tumeh et al., 2014). Attack by immune system in response to ICB produces biological effects and drug kinetics in cancer patients that are different from our previous experience with classical cytotoxic drugs and targeted agents in oncology. Peculiar patterns, such as durable and/or delayed ⁎

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responses, pseudoprogressions (Wolchok et al., 2009) and hyperprogressions [anedoctal rapid progressions observed in around 9% of patients treated with anti-PD-1 and anti-programmed death-ligand 1 (PDL1)] (Champiat et al., 2017) have occasionally been described, rendering the interpretation of changes in tumor burden a challenging issue. Furthermore, concomitant or sequential radiotherapy has occasionally been shown to reduce the size of some distant metastatic lesions away from the irradiation field (the abscopal effect), further contributing to the complexity (Weichselbaum et al., 2017). A need for more accurate and reproducible evaluation of clinical activity and drug efficacy with these new molecules has recently been addressed through development of immune related response criteria (irRC), which were modified from the World Health Organization (WHO) criteria (Wolchok et al., 2009) and the recently updated immune Response Evaluation Criteria In Solid Tumors (iRECIST) (Seymour et al., 2017). While irRC is based on bidimensional measurement of target lesions (Wolchok et al., 2009), iRECIST proposes unidimensional measurement of lesions (Nishino et al., 2013). New

Corresponding author. E-mail address: [email protected] (M. Porcu). Contributed equally: co-first authors.

http://dx.doi.org/10.1016/j.critrevonc.2017.09.017 Received 27 June 2017; Received in revised form 13 September 2017; Accepted 30 September 2017 1040-8428/ © 2017 Elsevier B.V. All rights reserved.

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squamous cell carcinoma patients treated with anti-PD-1 (nivolumab) (Yoshida et al., 2017). Pseudoprogression has also been described in melanoma patients with spinal metastases treated with concomitant ICB, stereotactic ablative radiotherapy (SABR) and surgery (Jhawar et al., 2017), further complicating the evaluation and interpretation of treatment response. The discrimination between pseudoprogression and true progression appeared much easier with hybrid imaging than with classical imaging techniques (i.e. computed tomography (CT)) scan and magnetic resonance, (MR). A neutral amino acid tracer, 11C-methyl-L-methionine (11C-MET) Positron Emission Tomography (PET) was capable of differentiating between an immune response (characterized by a low tracer uptake) and a tumor progression (with high tracer uptake) (Chiba et al., 2012). Ultrasound imaging efficiently revealed pseudoprogression occurring in superficial metastases (i.e.: cutaneous and nodal) from melanoma patients under the anti-PD-1 nivolumab, with a pattern of decreased blood flow followed by a reduction of the tumor size (Imafuku et al., 2016). Considering that pseudoprogression may represent a surrogate for clinical benefit and for an increased survival after ICB, its systematic report in clinical trials of immunotherapy may aid in further elucidating the dynamics of the interactions between the tumor and the immune system during ICB. Nonetheless, some critical and practical aspects should be taken into account when evaluating pseudoprogression. The probability of the occurrence of a delayed response that might lead to the continuation of ICB should be weighed against the risk of overtreatment. Pseudoprogression should not be accompanied by a deterioration of the clinical or performance status (Seymour et al., 2017), which may mirror a true progression of the disease. Evaluation of pseudoprogression with bidimensional measurements (as per iRECIST) through classical imaging techniques might also be affected by the observed wider measurement variability with a higher rate of misclassification for response and progression (Nishino et al., 2013; Erasmus et al., 2003; Nishino et al., 2011; Oxnard et al., 2011; Zhao et al., 2009). Moreover patients with progressive metabolic disease (PMD) evaluated at [18F]fluorodeoxyglucose (18F-FDG) PET/CT were shown to be mistakenly classified in case of pseudoprogression (Sachpekidis et al., 2015).

parameters have been introduced, including the patient’s clinical status and unconfirmed progressive disease (iUPD), which requires consecutive evaluations (Seymour et al., 2017). The principal aim of this review is to discuss critical aspects and challenges for imaging in patients receiving cancer immunotherapy by focusing on clinically relevant routine and research techniques. 2. Pseudoprogression Tumor growth during or after administration of anti-tumor therapy is commonly considered equivalent to treatment failure in oncology. Radiologic enlargement of the tumor burden, followed by regression (named pseudoprogression) was first seen in central nervous system (CNS) malignancies following treatment. In brain tumors an initial increase in contrast enhancement with the appearance of edema can be followed by stabilization or regression of neoplastic lesion(s) (Brandsma et al., 2008; Pope et al., 2006). Pseudoprogression was observed in up to 10% of cancer patients shortly after starting ICB treatment (Wolchok et al., 2009). This peculiar pattern of response appears after T cell recruitment and infiltration into the tumor, which also generates edema or necrosis (Chiou and Burotto, 2015; Di Giacomo et al., 2009) and partially explains the initially detectable increase in tumor size. If tumor shrinkage is detected at the subsequent assessment then this is defined as pseudoprogression. One of the major innovations introduced by iRECIST was a requirement to confirm tumor enlargement after a minimum of 4 weeks from the last evaluation (Seymour et al., 2017). Pseudoprogression can also occur in parallel with the appearance of new lesions, usually associated with edema and the presence of extensive immune infiltrates. It is also seen when tumor growth occurs before sufficient immune infiltration in the tumor (Hodi et al., 2016). This phenomenon is sometimes followed by atypical, delayed responses, which has been described for up to 15% of melanoma patients progressing under immunotherapy (Hodi et al., 2016). Importantly, pseudoprogression is associated with favorable long-term outcomes, particularly in melanoma patients treated with ipilimumab (anti-CTLA-4). The prevalence of pseudoprogression in patients treated with antiPD-1 or anti-PD-L1 was less frequent in bladder and renal cancer (< 2%) and lung cancer patients. However, most currently published studies evaluated treatment responses using conventional RECIST 1.1 criteria (Chiou and Burotto, 2015). A retrospective study of 54 advanced non-small cell lung cancer (NSCLC) patients treated with antiPD-1 therapy did not have a single patient who experienced pseudoprogression (Nishino et al., 2016). Patients with head and neck (H & N) cancer receiving anti-PD-1 (pembrolizumab or nivolumab) (Seiwert et al., 2016; Ferris et al., 2016) were also rarely observed to pseudoprogress. While these observations require confirmation in bigger cohorts, it is possible that this effect is, in part, due to the heterogeneous kinetics of immune activation with different ICB agents (i.e. anti-CTLA4 is thought to predominantly target the priming phase, while anti-PDL1 acts on the effector phase). True disease progression is defined as a confirmed increase in tumor burden during a radiologic exam following a previously detected iUPD, as suggested in iRECIST (Seymour et al., 2017). Confirmation of iUPD can be complicated by the possibility of delayed pseudoprogression (usually observed any time after 12 weeks of therapy) in contrast to early pseudoprogression (usually seen during the first 12 weeks of therapy). In melanoma patients treated with anti-PD-1 (pembrolizumab), the frequency of delayed and early pseudoprogression was very low (2.8% and 4.6%, respectively) (Hodi et al., 2016). Organ sites, concomitant treatments and timing of ICB administration all affect the evaluation of tumor burden during immunotherapy. Leukocyte infiltration and immune activation increase imaging contrast enhancement in the brain and thereby mimick tumor progression (Huang et al., 2015; Okada et al., 2015). Furthermore, radiotherapy induced tumor flare with pseudo- or rapid progression in lung

3. Immune related response criteria To date, the RECIST system 1.1 (Eisenhauer et al., 2009) represents the gold standard of the evaluation of response to treatments with the use of CT, MR and 18F FDG PET imaging techniques. Earlier in oncology, modified RECIST (mRECIST) criteria (Bruix et al., 2005) and the Choi Response Criteria (Choi et al., 2004, 2007; Choi, 2008) were introduced for the follow-up of patients with hepatocellular carcinoma (HCC) and gastrointestinal stromal tumor (GIST) respectively. These specific criteria were developed because the evaluation of the effects of the treatments needed to be integrated with additional data rather than only being based on the dimensional changes of neoplastic lesions. For example, in the mRECIST the disappearance of intramural arterial enhancement in all target lesions is an important parameter considered for the definition of a complete response (Bruix et al., 2005; Tirkes et al., 2013), whilst in GIST, the decreased tumor attenuation is also taken into account (Choi et al., 2004; Tirkes et al., 2013). Moreover, the PERCIST criteria (Wahl et al., 2009) used for PET/CT imaging, introduced the evaluation of the metabolic activity of the tumor as an additional factor to consider in the followup. As previously stated, ICB brought new challenges in medical oncology, for its peculiar mechanisms of action and patterns of response, compared to traditional cytotoxic and targeted agents. In 2009, Wolchok et al. (2009) proposed the irRC for the assessment of the tumor burden in patients with advanced melanoma treated with ipilimumab. In their retrospective study, authors were able to show a 14

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Table 1 irRC and iRECIST 1.1 criteria: patterns of response. irRC and iRECIST 1.1 patterns of response Complete Response (irCR in irRC; iCR in RECIST 1.1) Partial Response (irPR in irRC; iPR in iRECIST 1.1) Stable Disease (irSD in irRC; iSD in iRECIST 1.1) Unconfirmed progressive disease (iUPD; category presents only in iRECIST 1.1)

Progressive disease (irPD in irRC;iCPD in iRECIST 1.1;)

Total remission of all target and non-target lesions, including the lack of appearance of new lesions. These data need to be confirmed by another consecutive investigation performed no less than 4 weeks after the first one. A decrease of at least 50% in the total tumor burden compared to baseline. These data need to be confirmed by a consecutive imaging evaluation performed after at least 4 weeks. The change of the total tumor burden is reduced of less than 50% when compared with baseline or increased less than 20% when compared with the smallest recorded tumor burden (nadir). Increase in the total tumor burden of at least 20% compared to nadir. “Unconfirmed” refers to the initial dimensional increase that can be detected after 1 cycle of immunotherapy. This might reflect the activation of the immune response, mimicking a tumor growth. Further confirmation at imaging is needed. Increase in the total tumor burden of at least 20% when compared to nadir. In iRC this observation must be confirmed by a consecutive assessment performed not over 4 weeks form the first examination that showed the progression of the disease. In iRECIST 1.1, in order to confirm the disease progression, it must be evidenced a further increase in the tumor burden (≥5 mm) or a further increase of non-target lesions or the appearance of new target or non-target lesions in the next assessment after the examination where progression was previously observed (4–8 weeks).

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Measurements performed with iRECIST criteria were relatively more reproducible than the bidimensional criteria used for irRC (Eleneen and Colen, 2017; Nishino et al., 2014, 2015). These criteria can be used for the assessment of tumor burden during or after the treatment with ICB, but also with vaccines, cytokines and other immune checkpoint modulators (Henze et al., 2016). However a major limitation is that, to date, only few studies with small cohorts of patients have been performed using iRECIST (Eleneen and Colen, 2017). Examples of the evaluation of tumor response in patients treated with immunotherapy, by using iRECIST 1.1 are shown in Figs. 1–4. Moving to neuro-oncology, in 2015 the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria were published (Okada et al., 2015). They mainly follow the same guidelines of Response Assessment in Neuroncology (RANO) criteria (Eleneen and Colen, 2017; Wen et al., 2010). As well as irRC, iRANO evaluate the dimensional changes of the total tumor burden, obtained by the SPD of the target lesions. For every target lesion, the longest perpendicular diameters should be measured. Target lesions are enhancing measurable lesions that should measure at least 10 × 10 mm, and maximum five lesions can be taken into account (Okada et al., 2015; Eleneen and Colen, 2017). Non-target lesions are: enhancing measurable lesions smaller than 10 × 10 mm, enhancing non-measurable lesions and non-enhancing T2/FLAIR lesions at MR. The appearance of new target lesions after 6 months from the start of the treatment is considered tumor progression (Okada et al., 2015; Eleneen and Colen, 2017). The gold standard imaging method in neuro-oncology is MR and CT can also be used although with relative restrictions (Okada et al., 2015; Eleneen and Colen, 2017). In this case, five patterns of response are recognized: CR, PR, Minor Response (only used for low-grade gliomas), SD and PD. The main difference with RANO criteria is that the appearance of new lesions in a period of less than 6 months from the initiation of the treatment, in the absence of a tumor-related clinical decline of the patient, may not represent a true progression of the disease. In the latter case, immunotherapy should be continued and a new evaluation should be repeated in 3 months (Eleneen and Colen, 2017; Okada et al., 2015).

benefit in overall survival (OS) in patients having the following patterns of response (as defined by the new irRC criteria): 1) shrinkage in baseline lesions; 2) durable stable disease (SD); 3) response after an increase in the tumor burden and 4) response in the presence of new lesions. Even if based on the old WHO criteria (WHO, 1979), by evaluating the dimensional changes of the total tumor burden obtained by the sum of the products of the diameters (SPD) of the target lesions, irRC proposed a minimum size of 5 × 5 mm for the definition of a target lesion. Furthermore, the largest bidimensional diameters of each lesion should be measured as well. A maximum number of five cutaneous lesions and ten visceral lesions (no more than five lesions per organ) can be considered in this sum. Appearance of a new target lesion during the follow-up should be included in the total tumor burden measurement. On the contrary, non-target lesions do not contribute to the total tumor burden, even though in case of complete response (CR) they should be in complete remission. Four different classes of responses were proposed: Complete Response (irCR), Partial Response (irPR), Progressive Disease (irPD) and Stable Disease (irSD) (Wolchok et al., 2009; Eleneen and Colen, 2017) [detailed in Table 1]. Similar to RECIST 1.1. criteria, irRC evaluation can be done on almost all current imaging modalities including CT, MR and PET/CT. The major limitations of this method are: the absence of information on the nodal disease and the lower reproducibility of the bidimensional assessment when compared to the unidimensional one (Eleneen and Colen, 2017). In 2014 Nishino et al. (2014) proposed new criteria called iRECIST 1.1, recently updated by Seymour et al. (2017), trying to overcome the limitations of irRC. In this paper, a group of patients with advanced melanoma treated with ipilimumab was evaluated. The method for the assessment of lesions and target lesions differentiate iRECIST 1.1 from irRC criteria (Eleneen and Colen, 2017; Nishino et al., 2014, 2015) [detailed in Table 2]. In fact, the new criteria propose the evaluation of dimensional changes in the total tumor burden, obtained by the sum of the single longest diameters of all target lesions, considering a maximum of five lesions, up to two per organ. Target lesions should measure at least 10 × 10 mm. Nodal lesions can also be considered as target, if they measure at least 15 mm in the shortest diameter. In this case if a new target lesion appears during the follow-up, its longest diameter needs to be included in the total tumor burden. Non-target lesions do not contribute to the total tumor burden, but in the case of a CR, they have to be in complete remission. Usually, the follow-up for the assessment of the response to immunotherapy should be performed every 6–12 weeks (Seymour et al., 2017). There are five possible classes of response: Complete Response (iCR), Partial Response (iPR), Stable Disease (iSD), Unconfirmed Progressive Disease (iUPD) and Confirmed Progressive Disease (iCPD) (Tables 1 and 2).

4. Imaging techniques and cancer immunotherapy CT, MR and hybrid imaging (PET/CT and PET/MR) are the most important imaging techniques used in daily clinical practice in oncology. In the next paragraphs, we will present a general overview of the main aspects to consider for the evaluation of response to immunotherapy with some hints on the immune related adverse events (irAEs) that can be observed at imaging. 15

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Table 2 Differences between irRC and iRECIST 1.1 criteria. Differences between irRC and iRECIST 1.1 criteria

Number of categories

irRC

iRECIST 1.1

4 possible categories: 1. Complete response: irCR 2. Partial Response: irPR 3. Stable Disease: irSD 4. Progressive Disease: irPD

5 possible categories: 1. Complete response: iCR 2. Partial Response: iPR 3. Stable Disease: iSD 4. Unconfirmed Progressive Disease: iUSD 5. Confirmed Progressive Disease: iCPD Non-nodal: they should measure at least 10 × 10 mm (maximum 5 lesions, up to 2 per organ) Nodal: their shortest diameter should measure at least 15 mm Non-nodal: single longest diameter Nodal: shortest diameter Sum of the single longest diameter of non-nodal target lesion(s) and sum of the shortest diameter of nodal target lesion(s), including possible new lesions

Target lesions

They should measure at least 5 × 5 mm (maximum 5 cutaneous lesions and 10 visceral lesions, up to 5 per organ)

Assessment of the target lesions Total tumor burden evaluation

The largest bidimensional diameters Sum of the products of diameters (SPD) of target lesions, including possible new lesions

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is not the only one that should be taken into consideration. Changes in the composition of target lesions (for example the cavitation) and the enhancement behavior on CT after contrast medium infusion (for example the reduction of the enhancement as a signal of reduced tumor vascularization (Goel et al., 2011)) are always evaluated during the follow-up of cancer patients. Moreover, the limited spatial resolution of this technique often makes an accurate estimation of dimensional changes in daily clinical practice difficult. Hopefully, the development of computed assisted volumetric analysis of the lesions will be more helpful in the future. The irRC and the recently proposed iRECIST criteria have been designed to better evaluate the effects of ICB therapy on CT (Postow et al., 2015) (Fig. 1), while considering the already described peculiar patterns of response that can be observed at imaging. Dual Energy CT (DECT) is a novel interesting method that would help clinicians and radiologists to obtain useful additional information

4.1. CT CT is the most frequently used imaging technique in the follow-up of cancer patients. It enables a fast examination providing some information on the stage of the disease, on the dimension and on the morphological features of neoplastic lesions. It also allows for the evaluation of the surrounding structures and the number and location of metastatic lesions. The main limitations of this technique are: the use of ionizing radiations and the use of iodinated contrast medium that can induce some severe adverse reactions including contrast induced nephropathy (CIN), particularly in patients with chronic kidney disease (CKD) (Thomsen and Webb, 2014; ACR, 2016). Despite the fact that this technique is widely used for the follow-up of cancer patients, there are still some concerns about the best method to evaluate the effects of treatments administered in oncology. As mentioned above, it is generally accepted that the dimensional criterion

Fig. 1. Example of unconfirmed progressive disease (iUPD) using iRECIST 1.1 (Seymour et al., 2017) in a patient with a single target lesion. If after the first assessment the target lesion increases at least 20%, a second assessment should be done by 4–8 weeks. If in the second follow-up there is a further increase in the tumor burden (≥5 mm), a further increase of nontarget lesions, or the appearance of new target or non-target lesions, it will be classified as a confirmed progressive disease (iCPD). If the longest dimension will be reduced to less than 50% or increased to less than 20% compared to baseline, the response will be classified as stable disease (iSD). If the longest dimension of the lesion will be reduced to more than 50% compared to baseline, the pattern of response will be defined as partial response (iPR). If the target lesion disappears, it will be classified as complete response (iCR).

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Fig 2. Target lesion in a 73 year old woman diagnosed with adenocarcinoma of the lung. (a) The CT scan performed before the start of immunotherapy shows the presence of the tumor in the right upper lobe, with the longest diameter measuring 48 mm. (b) After six months of treatment with the anti-PD-1 nivolumab the longest diameter of the tumor measures 17 mm, a decrease of more than 50%, which corresponds to a complete response (iCR) based on iRECIST criteria.

resolution, MR is able to better visualize anatomical sites that are not well defined by CT, for example in the CNS, allowing for a more sensible identification of the meningeal carcinomatosis, usually hardly identified by CT. The limitations of this technique are related to the long time of the examination (with an average of 20–40 min for exam) and the use of gadolinium based contrast medium that can induce, although rarely, a condition of Nephrogenic Systemic Fibrosis (NSF), especially in patients with GFR < 60 ml/min (Thomsen and Webb, 2014; ACR, 2016). Similarly to CT, the main features analyzed by MR in the follow-up are the size of the lesion and/or the appearance/disappearance of metastatic lesions. Taken singularly, these data are not sufficient for a correct interpretation of responses to treatments. When using MR, irRC and iRECIST criteria are used for the follow-up of patients treated with ICB. Additionally iRANO criteria should be used in case of tumors localized in the brain.

during the follow-up of cancer patients, revealing quantitative and qualitative changes of the intratumoral vascularization. Due to the use of X-rays beam at different kiloVolt (kV) values, iodinate maps can be obtained, showing the accumulation of the contrast medium inside the tumor and reflecting the intratumoral vascularization (Saba et al., 2015). Quantitative and qualitative changes of this parameter can reflect different effects of the treatment(s). For example, a decreased total iodine uptake was observed in patients with advanced melanoma responding to targeted therapy with BRAF inhibitors (Uhrig et al., 2015). 4.2. MR MR is another widely used technique for the evaluation of the tumor burden, especially in the CNS and in the liver, particularly in HCC. It is also broadly used for the local staging of H & N masses, rectum and gynecologic tumors. Due to its intrinsic high spatial and contrast

Fig. 3. Example of lasting stable disease (iSD) based on iRECIST 1.1 criteria in a 72 years old woman with adenocarcinoma of the right hilum and disseminated bilateral lung parenchymal metastases, treated with the anti-PD-1 nivolumab from January 2016 to August 2016, when the treatment was interrupted for toxicity. (a) The non-contrast CT scan performed before the beginning of immunotherapy shows the presence of the tumor in the right hilum, with the longest diameter measuring 73 mm. In this slice, multiple nodular parenchymal metastases are evident on the left lung (head arrows). These lesions resulted unchanged in dimensions in the following CT controls. All the nodular metastases localized in both lungs measure less than 10 × 10 mm, thus they are not considered in the iRECIST 1.1 evaluation. (b) Three months after the beginning of the therapy with the anti-PD-1 nivolumab, the longest diameter of the tumor measured 79 mm, showing an 8% increase of the longest diameter of the tumor, corresponding to iSD. (c) The non-contrast CT executed on June 2016 confirmed iSD. (d,e) The CT scans perfomed on November 2016 and January 2017 showed iSD despite the interruption of nivolumab.

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Fig 4. Target lesion + non-target lesion in a 56 years old woman with adenocarcinoma of the left lower lobe of the lung. (a) The CT scan performed before the start of immunotherapy with the anti-PD-1 nivolumab shows the presence of the tumor in the left lower lobe, with the longest diameter measuring 70 mm. (b) After three months of treatment the longest diameter of the tumor measures 90 mm, an increase of more than 20% of the tumor longest diameter, which corresponds to unconfirmed progressive disease (iUPD). Other non-target lesions (arrowheads) showed increased dimensions when compared with the previous examination.

its use in this field. The majority of papers represent case reports or studies performed on small cohorts of patients. For example, Perng et al. (2015) showed that 18F-FDG-PET is useful for staging, response assessment and prognosis of melanoma patients, especially for the detection of adverse reactions. Higuchi et al. (2016) reported that 18F FDG-PET was useful for the evaluation of response to nivolumab in a 77 year old patient with NSCLC. On the other hand, Gilles et al. analyzed 7 patients with metastatic renal cell carcinoma and found no correlations between changes of glucose metabolic rate (MRglu) and different responses, neither with CT imaging, OS and progression-free survival data (Gilles et al., 2013). In recent papers, Bauckneht et al. (2017) and Guldbrandsen et al. (2017) suggested that the role of PET imaging in ICB therapy still needs to be clarified and deeply investigated. Another commonly used radiotracer in clinical practice is 18FFluoro-Ethyl-Tyrosine (18F-FET). It is an artificial amino acid that is absorbed by neoplastic cells, but not incorporated during the protein synthesis and is used for the evaluation of brain tumors (Dunet et al., 2012). This technique is widely used in neuro-oncology (Galldiks et al., 2017), and recently Kebir et al. (2016) showed its potential to identify psedoprogression in patients with brain metastases from melanoma in treatment with ipilimumab or nivolumab. Considering that the activity of ICB is directed to the activation of T cells against neoplastic cells, new radiotracers able to directly mark T cells have been ideated and tested in pre-clinical and early phase clinical studies. 1-(2′-deoxy-2′-[18F]fluoroarabinofuranosyl) cytosine (18F-FAC) represents the substrate to deoxycicline kinase (dCK), an important enzyme of the cytosolic deoxyribonucleoside salvage pathway. This radiotracer accumulates more greedily in cells that have an increased activity of dCK, i.e. in lymphocytes localized in lymphoid organs, such as lymph nodes, spleen and thymus (Radu et al., 2008; Kim et al., 2016). Another radiotracer similar to 18F-FAC is 2′-deoxy-2′-[18F] fluoro-9-β-Darabinofuranosylguanine (18F-F-AraG) that tends to selectively accumulate deoxyguanosine kinase (dGK), a dCK related mitochondrial enzyme mainly expressed by activated T cells (Kim et al., 2016; Namavari et al., 2011). The combination of labeled monoclonal antibodies specific for T cells antigens and radioactive elements introduced the era of ImmunoPET (Higashikawa et al., 2014). The most studied targets are CTLA-4, PD-1, PD-L1 and CD3. In a pre-clinical study, a probe called 64Cu1,4,7,10-tetraazacyclododecane-N,N9,N0,N-tetraacetic acid-anti-mouse CTLA-4 mAb (64Cu-DOTA-anti-CTLA-4 mAb) was able to mark specifically CTLA-4, expressed mainly on activated T lymphocytes. Other probes have been ideated and used in pre-clinical studies in order to investigate the PD-1/PD-L1 pathway (Hettich et al., 2016). Larimer

Iron oxide nanoparticles, divided into superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO), are emerging as interesting tools for the evaluation of brain tumors by MR. USPIO such as ferumoxtran-10, ferumoxytol and ferucarbotran C tend to accumulate in the tumor interstitium and in peritumoral reactive cells, particularly in tumor-associated macrophages (Iv et al., 2015). The presence of SPIO can appear as a lack of signal on T2 and T2* weighted sequences. Due to these properties USPIO could be used to guide immune-modulating cancer therapies. 4.3. Hybrid imaging The idea of using a cellular or metabolic marker to determine the in vivo therapeutic effects of immunotherapy is at the basis of hybrid imaging techniques. The marker used is a radiotracer, a drug combined with a radioisotope that decays by emitting a specific path (usually γ–rays or positrons in diagnostic field) with a specific radioactive decay timing. The radiotracer tends to accumulate following its specific target, and this piece of information can be revealed through the use of specific detectors. These data can be then combined simultaneously or in a two-step modality with the morphological data derived from CT or MR. Nowadays, PET combined with CT (PET/CT) or MR (PET/MR) is the most used technique in clinical practice for the evaluation of the activity of neoplastic cells. The PET technique uses radiotracers that decay emitting positrons. When a positron (β+) gets in touch with an electron (β−), they annihilate and generate two γ–rays that travel following the same direction with opposite verse (180° angle of difference), at the energy of 511 kiloelectronVolt (keV). These γ–rays are then identified by the detection system placed around the patient (Uematsu et al., 2005). As said before, with this technique functional data are combined with the morphological information derived from CT or MR. Radiotracers used in PET have a very short decay time (usually less than 2 h), they have to be manufactured in loco using specific devices, called cyclotrons, and once produced they should be immediately administered intravenously to the patients. The most frequently used radiotracer in clinical practice is 18F FDG, with a half-life of 110 min, made by combining glucose with 18Fluorine (18F). 18F FDG is analog to glucose, and accumulates inside the cell. Once it enters into the cells, it is phosphorylated into 18FDG-6-phosphate, remaining inside without undergoing any further modifications (Kapoor et al., 2004). 18F FDG tends to accumulate in cells with higher metabolic activity, like neoplastic and inflammatory cells. 18 F-FDG PET is the main technique used in clinical trials to evaluate the response of immunotherapies, but some concerns exist concerning 18

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C. Solinas et al. 89 et al. (Larimer et al., 2016) tested the Zr-p-isothiocyanatobenzyldeferoxamine-CD3 on mice in a pre-clinical study to selectively detect CD3, an antigen that is part of the T cell receptor complex. The first-in-human PET imaging study was recently presented by Bensch and colleagues at the Annual Meeting of the American Association for Cancer Research in 2017 (Bensch and Veen, 2017). The PD-L1 antibody 89Zr-atezolizumab, a radiotracer able to bind to PD-L1 was infused. Investigators ran a study including patients with locally advanced or metastatic bladder cancer, NSCLC or triple negative breast cancer treated with the anti-PD-L1 atezolizumab and undergoing serial imaging exams until disease progression (NCT0245398) (Bensch and Veen, 2017). Tumor response assessment was done every six weeks according to RECIST 1.1. Authors showed that the radiotracer accumulated in lymphoid tissues such as liver and spleen, and in sites of inflammation. In tumors, the drug accumulated heterogeneously, also in the cases previously defined PD-L1 negative by immunohistochemistry. Tumor uptake of the radiotracer correlated to response evaluated by RECIST 1.1. Although most of the available studies on the Immuno-PET are preclinical, the observed results are encouraging and promising. The goal of Immuno-PET would be to become an invaluable tool for the imaging follow-up and, ideally, for the identification of patients likely to respond to cancer immunotherapy.

Pattern of irAEs might differ based on the type of ICB administered, as shown in melanoma patients (Robert et al., 2015). Hypophysitis was more frequent in patients treated with the anti-CTLA-4 ICB, whilst pneumonitis was more prevalent in patients treated with anti-PD-1. Moreover, the presence of irAEs can represent a good sign of response to immunotherapy: Bronstein et al. (Bronstein et al., 2011) retrospectively analyzed images and medical records of 119 patients with metastatic melanoma in treatment with ipilimumab. Patients with radiological manifestations of irAEs had an improved clinical benefit when compared with patients not experiencing these toxicities. 5. Discussion and conclusions Assessment of the changes of the tumor burden during cancer immunotherapy remains challenging. A variety of peculiar aspects such as delayed and atypical responses, pseudoprogression, hyperprogression and the possible occurrence of an abscopal effect (in patients treated with radiotherapy) should be taken into account (Schoenfeld, 2016). Nevertheless, high variability and/or imperfect accuracy, partly due to the absence of a consensus on standardized approaches for image acquisition, post-processing and analysis might affect this evaluation. Timing of the response evaluation represents a crucial point particularly in the case of PD, requiring further confirmation with an additional exam to be performed after at least four weeks and no later than eight weeks (Seymour et al., 2017). Histological examination of progressive lesions might aid in clarifying doubtful cases in order to assess whether the increase in the size is caused by an inflammatory infiltrate or by a true progression (Ribas et al., 2009b; Bearz et al., 2016; Horvat et al., 2017). Furthermore, accurate identification of true disease progression from radiation damage or inflammatory response might be achieved by novel approaches including diffusion, perfusion, and metabolic imaging. Increased reporting of immune-related response and irAEs in ongoing trials is necessary to determine whether pseudoprogression, durable SD and/or some toxicities might be confirmed as a surrogate for clinical benefit and increased OS. One of the questions raised from our review would be whether there is an ideal imaging method for the evaluation of tumor burden in cancer patients treated with immunotherapy. At the moment, we have no clear information in this regard. However, the use of traditional imaging methods (CT and MR) and hybrid imaging techniques (PET/CT and PET/MR), with the use of proper criteria (irRC or irRECIST and iRANO) can help clinicians in assessing the responses to immunotherapy more reproducibly. The ongoing and future research, especially in the hybrid imaging domain, will provide additional information on the tumor infiltration by immune cells (i.e.: effector T cells) that can be re-activated by immunotherapy. Results emerging from studies with PD-L1 specific radiotracers are encouraging and may represent useful tools for the selection of candidate patients to immunotherapy in the near future.

4.4. Immune related adverse events Lastly, it is important to underline that immunotherapy can generate clinically evident adverse reactions (such as lung interstitial disease, colitis, thyroiditis, arthritis and hypophysitis) or not-clinically evident adverse reactions such as hepatitis, pancreatitis, myositis, fascitis, benign or sarcoid-like lymphadenopathy and retroperitoneal fat haziness (Weber et al., 2012; Horvat et al., 2015; Michot et al., 2016; Kim et al., 2013a,b; Rao and Grumett, 2016; Min and Ibrahim, 2013; Albarel et al., 2015; Tirumani et al., 2015). Many of them, such as the ipilimumab-associated colitis (Kim et al., 2013a), hepatitis (Kim et al., 2013b), alveolitis (Rao and Grumett, 2016), adrenalitis (Min and Ibrahim, 2013) and hypophisitis (Albarel et al., 2015) are evident on imaging and should always be well documented and reported during the imaging follow-up. A retrospective study conducted on 147 consecutive patients with advanced melanoma treated with the anti-CTLA4 ipilimumab (given for 4 cycles at the dose of 3 mg/kg) (Tirumani et al., 2015) revealed that irAEs were observed in one third of the patients. Imaging criteria for organ-specific irAEs were followed, based on previous findings. The most common radiographically evident irAE was colitis, found in 19% of patients. Different types of colitis were identified: diffuse pancolitis and segmental colitis associated with diverticulosis, fluid-filled colon, mesenteric vessel engorgement and bowel wall thickening (> 4 mm irrespective of distension), or increased mucosal enhancement on contrast-enhanced CT scan of the abdomen (Kim et al., 2013a; Kirkpatrick and Greenberg, 2003). Sarcoid-like lymphadenopathy (with a 5% prevalence) appeared as a new bilateral symmetric lymphadenopathy of mediastinal and hilar nodes in the absence of any documented infection and in the presence of responses in other sites (Bronstein et al., 2011; Wolchok et al., 2009). Pneumonitis (with a 5% prevalence) was defined whether new consolidative or ground glass opacities inconsistent with the features of metastasis were detected (Eckert et al., 2009). Hepatitis (hepatomegaly, with heterogeneous parenchymal enhancement and periportal/gall bladder edema (Kim et al., 2013b)), thyroiditis (increase in the size of the thyroid with heterogeneous enhancement or new diffuse FDG uptake on PET) and pancreatitis (novel focal or diffuse pancreatic dimensional increase, without a focal lesion suspicious for metastasis (Di Giacomo et al., 2009)) were less commonly observed. Noteworthy development of irAEs occurred in less than 3 months in 76% of patients and the resolution of irAEs was observed after a median time of 2.3 months.

Disclosure All authors declare no conflict of interest. Funding This work was partially supported by a grant from the Belgian FNRS-Opération Télévie, and Les Amis de l’Institut Bordet. The study funders had no role in the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, nor the decision to submit the manuscript for publication. Ackowledgments Cinzia Solinas and Pushpamali De Silva are fellows of the Belgian Fund for Scientific Research (FNRS)-Operation Télévie. 19

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