PET/CT in Immune-Checkpoint Inhibitor Therapy: History
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Experts in nuclear medicine, thoracic oncology, dermatooncology, hemato- and internal oncology, urological and head/neck tumors performed literature reviews in their respective field and a joint discussion on the use of PET/CT in the context of ICI treatment. The aims were to give a clinical overview on present standards and evidence, to identify current challenges and fields of research and to enable an outlook to future developments and their possible implications. 

  • immune checkpoint inhibitor
  • non-small cell lung cancer
  • melanoma
  • lymphoma
  • head and neck cancer
  • renal cancer
  • immunotherapy-related adverse event
  • pseudoprogression
  • tracer
  • CAR-T

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.

SUV (standardized uptake value)

Quantitatively describes the glucose metabolism of a lesion. Regional radioactivity concentrations, determined by the dose administered, the decay of the nuclide and patient’s weight.

SUVmax (maximum standardized uptake value)

Represents the most intensive 18F-FDG uptake in the tumor, maximum SUV value of a region based on a single voxel value only. Often used as a parameter for nuclide uptake, but may be misleading, as it represents only a single voxel value. Thus, it is susceptible to noise, dependent on image resolution, and on the voxel of interest (VOI) definition [4]. An advantage of SUVmax is that placement of the VOI is not critical.

SULpeak (standardized uptake value corrected for lean body mass)

Measured in a 1 cm3 volume around the hottest voxel in the tumor. Is considered a more stable alternative to the noise-susceptible measurement of the SUVmax [5].

MTV (metabolic tumor volume) *

Represents the volume of a tumor lesion with increased 18F-FDG uptake. Whole-body (wb) or total (T) MTV has been defined as the sum of the individual MTVs of all lesions with SUV ≥ 2.5 [6] and has been shown to be a particularly strong prognostic factor in pre-ICI treatment melanoma and NSCLC patients [6][7][8][9][10]. Concerning early response assessment in NSCLC, the increase in wbMTV six weeks after ICI initiation indicated poorer outcomes even in the case of stable disease by CT assessment [11].

TLG (total lesion glycolysis) *

Defined as the product of the MTV and the mean SUV, integrating the tumor-related metabolic activity and tumor volume. In contrast to the SUV, it does not describe the maximum or average glucose turnover at a specific point, but rather the glucose turnover of all lesions. Metabolic tumor response as assessed by TLG may be a more precise predictor of prognosis than MTV or SUVmax [12].

* 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].