2.1 Introduction

Immunotherapy is used to improve a patient’s immune response to cancer cells, on the basis of the concept of immune surveillance, by activating both cell-mediated and humoral immunity to fight cancer. Immunomodulatory monoclonal antibody therapy utilizes preformed monoclonal antibodies directed against molecular targets to regulate T-cell activation. There are three main mechanisms involved in this kind of therapy: antibodies directed against the programmed death protein 1; (PD-1)/programmed death receptor ligand 1 (PD-L1). The mechanism is to block the PD1 receptor in the lymphocyte, while anti PDL1 is localized in the oncologic cell. The most common anti-PD1 and PDL1 drugs are: nivolumab, pembrolizumab, or atezolizumab.

The other involved mechanism is to block CTLA-4 in the T lymphocyte, and the main drug using this mechanism is imiliprumab (Fig. 2.1).

Fig. 2.1
An illustration of an A P C T cell interaction and the tumor microenvironment. The dendritic cell attacks the T cell after its activation via the C T L A 4 blockade, the receptors of the T cell combine with the tumor cell forming the P D 1 blockade.

Aleksandra Filipovic, 2017. Mechanism of action of immune-oncology agents. Recovered: https://cancerworld.net/e-grandround/the-role-of-immunotherapy-in-treating-solid-cancers

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The number of these drugs are increasing exponentially during the last time and also the indications and combination with chemotherapy and radiotherapy. In below figures, we see the main drugs approved in the USA by FDA for immunotherapy up to December 2018.

An illustration of U S F D A approved immune checkpoint inhibitors. The various carcinomas include squamous cell head and neck, malignant melanoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma, hepatocellular carcinoma, renal cell carcinoma, d m M R cancer, and cervical cancer.

US approved immunotherapies brief overview of the approved immune-checkpoint inhibitors. The information on U.S. FDA approved immune-checkpoint inhibitors is based on the FDA approved package inserts (USPI) and is complete as of 9th March 2019. Countries other than the USA may have variations in approvals as to the overview in this article. Recovered: https://medi-paper.com/us-fda-approved-immune-checkpoint-inhibitors-approved-immunotherapies/

2.2 Patterns of Response

4 illustrations of patterns of response of the radiotracer in the body. The patient has dots marked over the upper portion of the body.

According to the Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumor, there are four patterns of interest: (a) pseudoprogression; (b) hyperprogression; (c) dissociated response; (d) durable response.

2.2.1 Pseudoprogression

Interpretative criteria in CT By restoring an efficient antitumor T-cell response, immunotherapy can be followed by pseudoprogression which is defined as an objective response following initial disease progression. For CT (computed tomography) based on these observations, new specific response criteria have been developed, a consensus guideline-iRECIST was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) in cancer immunotherapy trials, including immune-related response criteria (irRC); defining the concept of unconfirmed progressive disease (uPD) that may be confirmed by a new radiological evaluation up to 12 weeks later [1]. This concept can only be considered when there is a clear clinical benefit (CB) of the patient meaning that we can see transient enlargement of tumors or the presence of new lesions and after sometime the tumor will respond to therapy. This pseudoprogression is expected in 15% of the patients treated with Ipilimumab and in 10 % of the patients treated with pembrolizumab in NSCLC.

To evaluate response to treatment we have different articles published. Hodi et al. [2] conducted a study-wide analysis and found that 12% of patients (51 of 411 patients) with melanoma treated with pembrolizumab were classified as responders or as having stable disease by immune response criteria [3]. Basically, four different forms of treatment response have been reported.

  1. 1.

    Reduction in tumor size after treatment initiation in comparison to baseline.

  2. 2.

    Initial increase of tumor size and/or new lesions followed by a decrease that meets criteria for partial or complete response in comparison to baseline.

  3. 3.

    Initial increase in tumor size and/or new lesions followed by a stable course.

  4. 4.

    Almost stable tumor size without any significant changes.

This pattern of increasing size is confirmed by biopsy as inflammatory cell infiltrates or necrosis, with subsequent decreased tumor burden.

Interpretative criteria in PET CT An iconic publication in EJNMMI: “FDG PET/CT for assessing tumor response to immunotherapy: Report on the EANM symposium on immune modulation” [4] includes these response criteria including a new category of unconfirmed progression (iUPD) to be confirmed by a further follow-up scan. This can also include identification of new lesions. A good approach that I think is the best approach should consider these categories:

  1. 1.

    Complete metabolic response (CMR) when there are no more detectable tumoral lesions in the 18 FDG PET/CT.

  2. 2.

    Partial metabolic response (PMR) when there is a diminution of 15–25% of basal SUV after the first cycle and of 25% of the basal SUV after 2 cycles.

  3. 3.

    Stable metabolic disease (SMD) decreases in less than 15% in SUVmax values or a decrease in 25% of the uptake after at least 2 cycles.

  4. 4.

    Progressive metabolic disease (PMD) is defined as an increase in SUVmax of ≥25% from baseline imaging or the appearance of new metastatic lesions.

A good correlation between metastatic and new hypermetabolic lesions could be the application of the Heidelberg criteria, they describe a sensitivity (correctly predicting CB) of 84% and a specificity (correctly predicting No-CB) of 100%; this group uses functional size (the size of the lesion (in centimeters) as measured on the fused PET/CT images). This cut-off was lower for lesions with larger functional diameters:

  1. (a)

    Four new lesions of less than 1 cm

  2. (b)

    three new lesions larger than 1.0 cm

  3. (c)

    two new lesions larger than 1.5 cm

Although this approach is really practical, this work was done only for ipilimumab in melanoma, necessitating to validation for other drugs [5].

9 axial sections of the abdominal region with fluorescence seen inside the bowel loops. 3 full body PET C T scan with dark areas in the brain and the urinary bladder.

The figure below is of a 45 years old male with renal cell carcinoma treated with immunotherapy, pembrolizumab and axitinib after the first PET/CT. Inital follow-up PET/CT showed increase in uptake and size of the bone metastasis with subsequent decrease in uptake after 6 months with good response to treatment. We can also see a new increased uptake lesion in 2nd PET CT located in right sacumo, and other bone images

2.2.2 Hyperprogression

It is defined as an acceleration on tumor growth, there should be a duplication on tumor size in less than 2 months with clinical detrimental of the patients. The incidence is approximately in 15 % of the patients (5 % in patients with less than 65 years old and 20% in older patients). It is more common in patients over 65 treated with anti-PD1/PDL1 and in NSCLC, when this situation is suspected, the treatment should be immediately changed [5, 6].

Hyperprogression was observed in 29% of patients with head and neck cancer treated with antiPD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases [6].

Hyperprogressive disease in NSLC was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% vs 42.6%) [7].

Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors [1].

The biological rationale may be related to that several primary and adaptive mechanisms of resistance to immunotherapy have been described. Response to immunotherapy seems to be conditioned by the infiltration of tumors by activated T-cells, other mechanism could be the absence of tumor recognition by T-cells, due to the lack of immunogenic tumor antigens, much more investigation should be done in this area.

A table with SUV maximum take on 7 December 2021, 28 June 2022, and 7 December 2022. The row represents the values for the sacrum, left iliac crest, ninth dorsal vertebrae, eighth rib, first lumbar vertebrae, third lumbar vertebrae, and tenth dorsal vertebrae.
4 full-body PET scans with the luminescence of the radiotracer in the region of higher metabolism and tumor. The most intense regions are the brain, liver, and urinary bladder.

Male 61 years old. Lung carcinoma treated with nivolumab. In the upper image we can see definite progression in comparison with lower images

Even with increasing published data on hyperprogression, its definition is not consensual. Some authors used only radiological criteria, based on the variation of three-dimensional or unidimensional measurements of tumor burden over time to evaluate the rate of tumor growth before and after immunotherapy initiation. However, there is no definite evidence of hyperprogression regarding metabolic imaging, most of the reviewed bibliography is supported on CT findings. In this point PD (progressive disease) is the most practical approach and doubling size in CT, for suspecting hyperprogression on 18F PET CT.

Dissociated Response

It is defined by a decrease or stabilization in some tumor sites with a concomitant increase in other sites.

Frequency: up to 10%.

It has better prognosis than homogeneous progression and these patients can benefit from adding other treatments like radiotherapy, surgery, or interventional radiology treatment.

It reflects the heterogeneity of tumors as well as their environment.

4 axial sections of the thoracic and abdominal region with the fluorescence of the region around the heart and liver. 2 full body PET scan indicates the intensity of fluorescence in the urinary bladder.

49 y Fem patient with relapsed Lung (NSCL) cancer treated with immunotherapy, after 6 months, we see good response in lung images, but there is a new increased uptake in right suprarenal gland, confirmed by surgery to be a small metastasis of 1.2 cm. Upper file: after 6 months treatment new PET CT

2.2.3 Durable Response

Female 60 y patient with melanoma resected and increased subcutaneous increased uptake (local persistent disease with increased uptake stable during 3 years.

6 PET scans of the lower limb of the patient have a bright intensity beneath the knee joint indicative of cancer.

Immunorelated Adverse Effects (irAE)

With these new drugs, more often with anti-PD1, there are adverse events related to immune activation, these effects are radically different from adverse effects related to cytotoxic drugs. Their presentation can range from mild and manageable, to severe and life threatening if not recognized early and treated with appropriate measures such as corticosteroids [8].The sensibility of PET CT for their diagnosis is much better than with others imaging modalities (CT), and the rapid identification and quick therapy, with immunosuppressive treatments, such as corticoids or TNFα antibody, improves patients evolution and allows to go on with the treatment [9]. Different irAE are more frequently seen with different drugs, e.g., ipilimumab, the first antibody approved by FDA, is seemingly more common with colitis and hypophysitis, while pneumonitis and thyroiditis are more common with nivolumab and pembrolizumab [10]. According to clinical reports, irAEs may occur at any time and cover multiple organs during the therapy (Fig. 2.2).

Fig. 2.2
An illustration of a human body with the effect of tracer in the regions includes neural with S N T, hepatotoxic or hepatitis, dermatological involves rash and pruritus, hypophysitis, Thyropathy in the endocrine glands, pneumonitis in respiratory, C R S in holistic, and diarrhea in G I.

irAEs can affect almost each organ system. Most of our organs may be affected with immune-related adverse events (irAEs), such as skin, liver, lung, pituitary, thyroid, gastrointestinal tract, and even the central nervous system. The severity of irAEs can range from mild and self-z. Available: Diagnosis and Management of Immune Related Adverse Events (irAEs) in Cancer Immunotherapy nYi-HeLiua1Xin. https://doi.org/10.1016/j.biopha.2019.109437

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2.3 Mechanism

The involved mechanisms are suspected to be either a result of the induction of autoimmunity or a proinflammatory state [11]. Other situations related to the primary tumor are also supposed to be involved, like the tumor microenvironment (TME), immune infiltrate, adaptive immune response and neoantigen formation, so there are different incidences reported in different tumors.

A chart with a line written on it reads, tumor reactive T cells may modulate the production of antibodies by B cells and lead to antibody mediated diseases.

Mechanisms underlying irAE

2.4 18FPET CT and irAE

The possibility of identifying inflammatory changes with F-18 FDG PET CT allows us to better diagnose this situation. There are different irAE, and the focus should be on the ones that can be life threatening: 34% of the patients according to Fujii et al. [12]. In “Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience [11] experienced any grade of irAE, and 80% of them required systemic corticoids, and the most important conclusion related to this article is that this undesirable effects are associated to active immunostatus suggestive of potential clinical benefit for the patients. The incidence of these effects also is different according to the immune mechanism involved, and the frequency is with Anti CDLA 4: 54%; anti-PD1: 26%; anti PDL1: 13%. It is important for the imager to recognize the unique adverse events associated with immunotherapy to guide appropriate treatment and avoid potential imaging pitfalls that could be mistaken for metastatic progression of disease. The patterns that should be considered are:

  • Pneumonitis is a very rare adverse effect. It is more frequent in the patients with the use of anti-PD-1 than anti-PD-L1 or anti-CTLA-4. But the compounding of PD-1 and CTLA-4 blockade was reported significantly higher frequency of the pulmonary toxicity than either single immune-checkpoint inhibitors, up to 5–10% at any grade and 2% at 3–4 grade. It involves death risk. There are four radiological CT patterns described for this complication [13]: (1) cryptogenic organizing pneumonia (COP) in 65% of patients. (2) Non-specific interstitial pneumonia in 15% of patients. (3) Hypersensitivity pneumonia in 10% and (4) Acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 10%. Regarding the severity of the disease, there are 4 grades:

    • Grade 1 pneumonitis may be assessed by radiographic evidence and another CT may be repeated within 3–4 weeks to focus on the disease progression. Immunotherapy should be discontinued until improvement back to grade 1 or less, and administering prednisone under guidelines is essential for patients with grade 2 of pneumonitis. If pneumonitis is progressing to grade 3 or 4, it is suggested that immunotherapy should be ceased with the appropriate prescription of antibiotics and prednisolone. The median time to onset of pulmonary toxicity after initiation of immunotherapy is 2.3 months and tends to occur earlier in lung cancer (2.1 months) than in melanoma (5.2 months). Even after improvement of pneumonitis, occur with and without PD-1 antibody re-administration [14].

5 full body PET scans of the patient with fluorescence inside the chest cavity. 36 axial sections of the chest with massive intensity are present around the alveoli and the cardiac wall.

(a, b) Acute interstitial pneumonia in a patient treated with immunotherapy

A table of radiologic patterns according to i r A E. It is divided into C t patterns and C T features. The information on Acute interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, and hypersensitivity pneumonitis are exhibited.

  • Colitis (more frequently within 6–7 weeks): It is associated to death risk when not treated as soon as diagnosed. Diarrhea and colitis are the main symptoms of gastrointestinal toxicities. In patients receiving ICPis, the incidence of all-grade diarrhea is reported to be higher with anti-CTLA-4 therapy, up to 30%. High grade diarrhea is also reported when nivolumab pluses ipilimumab, with the incidence up to 9%. There are two different patterns associated with Ipilimumab: Diffuse Pancolitis, that should be treated with corticoids, and during the diagnosis we should make the differential diagnosis with colitis related to oral hypoglycemics drug: many nuclear medicine departments stop metformin 24 h before 18FDG PET CT to avoid this situation. And segmental colitis which is associated with diverticulosis, restricted to a segment of colon and the treatment should include antibiotics [15]. In the CT we can see mesenteric vessel engorgement, bowel wall thickening (> 4mm irrespective of distension), or increased mucosal enhancement contrastct enhanced CT scan [16].

    Male 66 years old renal cancer with pulmonary secundarism. Treated at first with sunitinib no answer, he started therapy with Nivolumab 6 months ago. We can see segmental colitis confirmed with endoscopy. Images courtesy of Dr. Marcelo Claria, jefe de Diagnóstico por imagen Sanatorio Allende. Córdoba-Argentina.

    2 full body PET C T scan with the luminescence of the tracer in the pancreas is exhibited. An axial section of the abdominal region has the tracer intensity in the pancreas and the urinary bladder.

  • Pancolitis after Pembrolizumab in a patient treated for melanoma. Images courtesy of Dr. Marcelo Claria, jefe de Diagnóstico por imagen Sanatorio Allende. Córdoba-Argentina

    2 PET C T scans with traces of the fluorescence of the radiotracer in the areas of the liver and bowel loops.
    2 full-body PET CT scans of the patient with fluorescence in the pelvic region. An axial section of the thorax has a bright intensity as indicated by an arrow.

  • Hepatitis: Starting at 3–9 weeks. The occurrence of hepatitis is less than 6% of patients receiving anti-PD-1 antibodies, about 7% of patients with CTLA-4 therapy and nearly 30% when CTLA-4 and PD-1/PD-L1 blockades are combined [17].

  • Adrenitis

  • Pancreatitis (−1%) in this case the typical pattern is increased diffuse uptake with the CT showing mildly enlarged pancreas with no peripancreatic inflammatory changes and rounded pancreatic contours that can be described as having the “sausage” appearance of autoimmune pancreatitis.

  • Hypophysitis for Aide et al. [4], suggest the importance of starting the PET/CT by including the whole of skull in patients treated with immunotherapy. Also magnetic resonance imaging (MRI) of pituitary gland manifests specific imaging characteristics of enlarged pituitary glands and stalks.

  • Thyroiditis: Thyropathy mainly includes primary hypothyroidism and hyperthyroidism, among which hypothyroidism is more common. Hypothyroidism generally develops at the 4th week with ipilimumab therapy and the 10th week in patients receiving nivolumab (more frequently between 7 and 20 weeks). It is very important to check that intense uptake deemed to be an immune-related sign was not present on the baseline scan, for example, diffuse thyroid uptake due to Hashimoto disease. Moreover 18F-FDG PET/CT can predict the development of thyroiditis with subsequent hypothyroidism before laboratory testing after immunotherapy with nivolumab for lung cancer [28].

  • Arthritis: shows diffuse periarticular FDG uptake in different joints like shoulders, elbow, wrists, hands, and hips.

  • Gastritis

  • Myocarditis

There are also other undesirable effects like dermatitis (such as rash, pruritus, and vitiligo but also may appear more serious effects like bullous pemphigoid, scleroderma-like skin changes, and severe cutaneous adverse reactions), fatigue, etc. not able to be recognized by 18FDG PET/CT.

It is also very important to compare previous studies, and to pay special attention to this irAE evolution in terms of metabolic behavior.

Incidence of irAEs with immunotherapeutic agents indicates an active immune status, suggestive of potential clinical benefit to the patient [12].

2.4.1 Therapy-Related Inflammation and Inverse Relation Liver SUV/Spleen SUV [18]

18F-FDG PET can help in the differentiation between progression and therapy-related inflammation, to define inflammatory changes it is important to consider particular patterns of tracer uptake [19]. Metabolic information provided by PET/CT is very important. And some items should be considered in lymph nodes and spleen. There are some important facts to consider regards lymph nodes:

Reactive nodes in the drainage basin of the primary tumor may be seen.

Reaction sarcoidosis like (5–7%) increased FDG uptake in mediastinal/hiliar nodes and may be in spleen. Symmetrical bilateral pattern of uptake in thorax, in enlarged hiliar/mediastinal lymph nodes suggesting sarcoidosis: lambda sign with or without portocaval nodes.

Preservation of fatty hilum.

15 axial sections of the thorax with increasing intensity are exhibited on the edge of the heart. A full-body PET scan indicates fluorescence in the organs of active metabolism and tumor.

In patients with good evolution with the previous characteristics, FDG avidity can be a marker of immune activation rather than progressive disease [20]

2.5 Conclusion

There are four patterns when reporting 18FDG PET CT after immunotherapy that should be considered (a) pseudoprogression; (b) hyperprogression; (c) dissociated response; (d) durable response. Immune related adverse events should be considered and reported, as well as therapy-related inflammation like sarcoidosis like reaction are immunotherapy-related findings. It is necessary to write a practical guide for reporting these findings in order to harmonize our results.