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1. Introduction

Positron emission tomography/computed tomography (PET/CT) constitutes a major progress in oncology imaging, as it augments CT with the additional dimension of metabolic activity. Primarily used in staging and to some extent in response assessment of various malignancies, research for additional applications of PET/CT is currently evolving towards prognosis estimation and prediction of response to certain therapies, especially in the field of immunotherapy [1].

Cancer immunotherapy through immune-checkpoint inhibitors (ICI) has revolutionized the world of medical oncology, achieving major and long-term treatment responses also in metastatic disease that would have been unthinkable only a few years ago. Fields of application of ICI therapies have rapidly expanded to different tumor entities and a multitude of ICI substances in various treatment regimens has subsequently become available [2]. Still, by far, not every patient responds to ICI therapies, and existing biomarkers do not allow to predict response precisely on an individual patient’s level. Thus, prediction and monitoring of response to ICI treatment has become a major research target in the recent years.

2. PET/CT in Immune-Checkpoint Inhibitor Therapy—Technical Aspects, Application and Research

2.1. Technical Aspects of PET/CT in Assessing Immunotherapy Response

The advent of ICI in the treatment of various malignant tumors constitutes a milestone in clinical oncology. However, the complex immunological response to these novel agents involving the tumor microenvironment has only been incompletely understood and poses a major challenge in molecular imaging strategies.

Accurate assessment of response to antineoplastic therapy is essential to recognize treatment failure at an early stage and to be able to adapt therapy timely. Classically, this would be indicated by an increase in number and/or size of tumor lesions [3]. Using positron emission tomography (PET), also the change in ¹⁸F-FDG uptake in malignant lesions as quantified by the standardized uptake value (SUV) can be used as a biomarker for therapy response. This metabolic biomarker dimension has been included in many oncological treatment concepts. A summary of quantitative biomarkers derived from PET/CT imaging that can be easily (semi)-automatically determined is shown in Table 1.

Table 1. Summary of quantitative biomarkers that can be derived from PET/CT imaging.

* In contrast to the estimation of SUVmax, determination of MTV and TLG depends on the placement of the VOI. Several approaches can be applied and need to be specified in the methods of the respective publication. Another practical problem with MTV and TLG is that it can be difficult or even impossible to apply in the case of a large number of metastatic lesions, since a VOI has to be created for each individual lesion. ICI: immune-checkpoint inhibitors; NSCLC: non-small-cell lung cancer.

In the context of ICI therapy, however, the efficacy of quantitative measurement of ¹⁸F-FDG uptake may be diminished and sometimes misleading. Enhanced ¹⁸F-FDG uptake can also be triggered by the activation of the tumor microenvironment with an increased influx and activity of immune cells like T-lymphocytes induced by ICI therapy itself [13,14]. In contrast to aerobic glycolysis in highly differentiated tissues, the so-called Warburg effect in more proliferative neoplastic tissues leads to an increase in anaerobic glycolysis, and thus to an increase in general glucose turnover [15]. At the same time, during immunotherapy, anti-PD-1 activation also stimulates the tumor microenvironment and consequently upregulates glucose transporter (GLUT) mRNA and GLUT proteins, leading to increased glucose consumption as a result of the immunological anti-tumor reaction [16,17]. This altered metabolic situation can conceal the actual treatment response and, under certain circumstances, even lead to false positive scan results. Therefore, new approaches to PET/CT assessment in patients receiving ICI therapy are required [18].

2.2. Standardizing Response-Assessment in PET/CT Imaging

Basic evaluation of therapy response using PET/CT can be accomplished using qualitative parameters, like the decrease or increase in metabolic of active tumor lesions. Such binary “good or poor” categorization is rather robust and can be used, e.g., for end-of-treatment assessment. Particularly complete metabolic response in PET represents an important individual decision-making criterion and generally indicates a favorable long-term outcome [19]. An example of such positive sustained response is shown in Figure 1. Similarly, the appearance of new lesions in follow-up is of higher clinical relevance than changes in preexisting lesions [20].

Figure 1. Complete metabolic response over two years visualized by PET/CT: 68-year-old woman with stage IV lung squamous-cell carcinoma (PD-L1 1%) having progressed after first-line chemotherapy, showing multiple liver, bone and lymph node metastases (a). The patient responded well to pembrolizumab monotherapy, with a PET/CT follow-up scan after one year (b) showing complete metabolic remission. Therapy was completed after two years, still in complete metabolic remission (c). PET/CT: positron emission tomography/computed tomography; PD-L1: programmed death-ligand.

However, an such approach does not allow a fine-tuned therapy assessment and is not suitable for clinical trials, where reproducible and standardized response data are warranted. In conventional CT, this led to the introduction of standardized response evaluation criteria in solid tumors (RECIST) using the classifications complete/partial remission (CR/PR), stable disease (SD) and progressive disease (PD) [21]. Concerning PET/CT, analogous criteria have been suggested, such as the “European Organization for Research and Treatment of Cancer (EORTC) PET Criteria” or more recently the “PET response criteria in solid tumors” (PERCIST) [5,22]. The aim of these assessment tools is to improve the clinical value of metabolic therapy assessment in terms of accuracy, reproducibility and to enable earlier response prediction as compared to conventional imaging techniques, e.g., by CT using size parameters [5].

One major point that needs to be considered in that context is that quantitative indices (including textural analysis) are dependent on the quality of the PET images. Results may vary distinctly between up-to-date imaging technology and equipment ten or twenty years old. Also, comparability is usually impaired when different reconstruction methodologies are used. Both can pose difficulties especially when comparing quantitative measures between institutions [23,24].

2.3. PET/CT and Atypical Response Patterns in Immune-Checkpoint Inhibitor Therapy

In ICI therapy, atypical response patterns pose additional challenges to classical radiological as well as PET-based response evaluations.

One such feature is pseudoprogression [25], which mimics disease progression, although it actually represents a hypermetabolic “flare-phenomenon” caused by the initial T-cell tumor infiltration. Frequently, such patients witness an objective response in the further course of therapy. Pseudoprogression is found considerably less frequently than effective disease progression, with reported rates below 10% [18,25].

Dissociated response is a similar atypical response pattern, with a mixture of lesions responding and progressing simultaneously [26,27]. Its reported frequency varies but might be similar to pseudoprogression, and prognosis is more favorable than for PD [26]; therefore, continuation of ICI treatment should be considered in such patients [27].

Durable responses to ICI therapy are not comprehensively defined but can occur both after primary partial or complete remission or out of stable disease [25]. As shown in Figure 1, 18F-FDG PET/CT can be used to determine long-term remission also on the metabolic level.

An unfavorable feature of atypical response is hyperprogression, which denotes patients presenting with an accelerated tumor growth rate early after ICI initiation, occurring in up to 7% [18,28]. It results in a very poor prognosis and is associated with widespread metastatic disease in the majority of cases [18,29]. Hyperprogression can be easily discovered by CT as well as by ¹⁸F-FDG PET-CT, using quantitative parameters, e.g., total lesion glycolysis (TLG) [29].

To account for these imaging challenges associated with atypical response patterns, RECIST criteria have been expanded to iRECIST, which is now commonly used for CT re-staging in ICI patients [30]. Analogously, several similar approaches have been suggested for PET/CT, such as iPERCIST [31], combining RECIST and PERCIST with the introduction of the response category “unconfirmed progressive metabolic disease”. Several other models, such as PERCRIT [32], PERCIMT [13], imPERCIST5 [33] (all for melanoma) or LYRIC (for Hodgkin lymphoma) [34] have been published. However, none of these criteria have been prospectively validated, and all are based on comparably small patient cohorts. Furthermore, differences in timing schedule, reference standards, tumor entities, outcome measures and response classification still limit the practicability of these response criteria in clinical routine.

2.4. PET/CT for Immunotherapy-Related Adverse Events

Immune-related adverse events (IRAE) such as thyreoiditis, pneumonitis or hypophysitis may lead to unusual patterns of ¹⁸F-FDG tracer uptake in various involved organs. These therapy-related findings represent possible pitfalls in PET/CT interpretation, especially as such side effects may not necessarily be clinically evident [35–37]. However, they can also have prognostic implications, as their occurrence may indicate a more favorable prognosis [38–40].

2.5. Novel Approaches to PET/CT Imaging and Tracers beyond ¹⁸F-FDG:

A novel approach for baseline PET/CT imaging and prognosis estimation apart from traditional staging and response criteria refers to textural features within the tumor lesions. Texture analysis means a systematic, computer-aided evaluation of image data with special regards to features like heterogeneity within one or between individual tumor lesions. Such biomarkers have been correlated with clinical outcome parameters and may pose a major step towards a truly personalized therapy approach. Promising first results have been reported in patients with malignant melanoma treated with vemurafenib and ipilimumab [41]. For lung cancer, similar data could be shown considering the fraction of necrosis within the tumor lesions, which was also linked to the presence of CD8-positive lymphocytes in histological samples [42].

As already discussed, a general problem concerning ¹⁸F-FDG as a tracer for cancer treated with ICI is that therapy itself leads to an influx of inflammatory cells leading to enhanced PET activity [43]. Thus, more specific radiopharmaceutical agents are being developed: Radiolabeled ICI like 89Zr-nivolumab or 89Zr-pembrolizumab as well as agents targeting interleukin-2 could aid in the selection of patients who will benefit from ICI-therapy [18]. Data on these substances are still limited to animal models and early-phase human studies; however, an initial trial using ⁸⁹Zr-atezolizumab for PET imaging showed very promising results assessing clinical response to PD-L1 blockade in 25 patients with locally advanced or metastatic bladder cancer, non-small-cell lung cancer (NSCLC) or triple-negative breast cancer. Interestingly, responses to atezolizumab therapy in these patients had a better correlation with the pretreatment ⁸⁹Zr-atezolizumab PET signal than with immunohistochemistry- or RNA-sequencing-based predictive markers [44]. Further clinical studies are ongoing and can hopefully be expected in the future.

A very interesting novel approach is based on the use of Zr-89-labeled minibodies that target CD8-positive T cells [45]. Since tumor-infiltrating T cells, in particular CD8-positive T cells, play an important role for initiating and mediating a response to ICI, the in vivo visualization of CD8-positive T-cell-rich tissue might be crucial for development of more effective ICI therapies. A subsequent clinical phase 2 study using ⁸⁹Zr-IAB22M2C for PET-CT imaging is ongoing among patients with Melanoma, Non-Small-Cell Lung Cancer, Renal Cell Carcinoma, and Squamous Cell Carcinoma of the Head and Neck, aiming to predict response to ICI (NCT03802123).

Another novel promising imaging approach was reported by Chatterjee et al., who developed highly specific radiolabeled peptides for PET imaging of PD-L1 tumor expression [46–48]. Preclinical studies suggest excellent imaging properties and the potential to significantly influence the standard clinical workflow in ICI-treated patients, as these radiopharmaceuticals can be used not only for the therapy guidance and monitoring but also for optimizing dose and therapeutic regimes in a very individual way [48]. Initial clinical trials are ongoing and results may be expected in the near future.

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This entry is adapted from the peer-reviewed paper 10.3390/jcm9113483