Elsevier

PET Clinics

Volume 15, Issue 1, January 2020, Pages 11-22
PET Clinics

18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Assessing Tumor Response to Immunotherapy in Solid Tumors: Melanoma and Beyond

https://doi.org/10.1016/j.cpet.2019.08.007Get rights and content

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Key points

  • Recent development of immune check-point inhibitors has fundamentally changed the landscape of treatment for several diseases that previously had a dismal prognosis and no effective therapies.

  • The complexity of the immune response and the diversity of targets challenges conventional conceptual frameworks used in selecting and monitoring treatment.

  • Imaging and tissue biomarkers are being actively sought but are constrained by the biological, spatial, and temporal heterogeneity of the processes

The era of immune check-point inhibitors

The importance of ICIs to the management of cancer was recognized by the 2018 Nobel Prize in Physiology or Medicine for discovery of key negative regulators (check-points) of the immune system; cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and programmed death (PD)-1, leading to the development of anti–CTLA-4 (ipilumumab)1 and anti–PD-1 (pembrolizumab)2 monoclonal antibodies as the first generation of ICIs. These agents have been supplemented by several other ICIs directed against PD-1

The challenge of predicting response to immune check-point inhibitors

The immune environment is extremely complex with multiple cell types involved, complex signaling pathways, and multiple effector mechanisms.10 The TME is also very important with factors including tissue hypoxia and low pH also influencing the ability of the adaptive immune response to control or eradicate cancer.11 There has been a great deal of work invested in the search for robust predictive biomarkers of response to ICIs.12 These have included analysis of blood and tissue factors. Most of

The challenge of monitoring response to immune check-point inhibitors

Unlike chemotherapy or radiotherapy, which lead to a reasonably predictable depopulation of cancer cells in responding patients, allowing morphologic measures of response such as the RECIST schema to be used to predict survival25 or targeted therapies that lead to rapid reduction of glycolytic activity detectable by PET,26 immunotherapy has increasingly been recognized to have a variety of novel response patterns.27 These include a temporary increase in apparent tumor burden followed by

Mechanistic considerations of immune response

The immune system plays a critical role in maintaining health by recognizing and responding rapidly to pathogens. It also plays an important role in identifying and killing cancer cells in which mutational changes are expressed as aberrant proteins, termed TAAs. In simplistic terms, the adaptive immune response to cancer involves the interaction between an antigen-presenting cell and T lymphocytes involving the major histocompatibility complex on dendritic cells, TAAs, and the T-cell receptor

Implications of the TME and mechanism of action of immune check-point inhibitors for PET imaging

Although it is convenient to think of FDG uptake in a primary tumor or metastatic site as representing an aggregation of proliferating cancer cells, it is clear that it represents a much more complex process. The metabolic reprogramming of cancer cells through oncogenic signaling, the effects of hypoxia, and the contribution of stromal cells, particularly those of an inflammatory phenotype, all contribute to the apparent intensity of FDG uptake in lesions. This finding is particularly relevant

The value add of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in response assessment

Despite the promise of ICI therapy, there is a significant burden of toxicity, which are termed immune-related adverse events (irAE).58 Because these are generally related to autoimmune phenomena and involve activation of the immune system, these are often readily recognized on FDG PET/CT.59 Most of these irAE occur relatively early during therapy and can be manifest as inflammatory changes on FDG PET/CT scanning before the onset of symptoms. Almost any organ can be involved but important sites

Summary

Despite the encouraging response rates and durability of response in patients deriving clinical benefit from ICIs, many challenges persist in providing prognostic information for patients, selecting patients for treatment with these agents, and knowing when to withdraw or escalate treatment, for example, by adding anti–CTLA-4 treatment to patients with an incomplete response to anti–PD-1 ICI. FDG PET/CT scanning shares some but not all of the limitations of anatomic imaging. Emerging data

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    Disclosure Statement: Professor Hicks is supported by a Practitioner Fellowship of the National Health and Medical Research Council of Australia (APP1108050). He holds shares in Telix Pharmaceuticals. The other authors have nothing to disclose.

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