Keywords

7.1 Introduction

Cancer immunotherapy has caused a plethora of new and important radiographic features that are imperative to understand when assessing tumor response and immune-related adverse events [1,2,3]. An approach to treating cancer by augmenting or generating an immune response against cancer cells, immunotherapy causes radiographic responses distinct from conventional cytotoxic chemotherapies [2, 3].

Objective imaging response criteria as measured by the World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were originally created to assess the effects of cytotoxic chemotherapy and are dependent on tumor shrinkage and absence of new lesions; however, these criteria do not perform well in assessing the effects of drugs with other mechanisms of action such as antiangiogenic therapies or immune therapies [1, 4]. Evaluation of tumor response to cytotoxic chemotherapy depends on tumor shrinkage within a few weeks of initiating treatment. In fact, in addition to the appearance of new lesions and increased tumor size, stable disease was at one point considered a treatment failure [4]. On the other hand, new tumor therapies with recombinant cytokines, cancer vaccines, and immunomodulatory monoclonal antibodies may demonstrate a delayed response, transient enlargement (transit flair up phase) followed by tumor shrinkage, stable size, or the appearance of new lesions [4]. Unique challenges associated with immunotherapy reflect delays in response and therapy-induced inflammation. Cancers after immunotherapy demonstrate confounding radiographic appearances with only 10% showing regression [4]. Typically, these tumors initially demonstrate a delay in response, including none or slow decrease in tumor size, increase in tumor size, and/or the appearance of new lesions which overtime become stable, decrease, or resolve without further treatment (Fig. 7.1). Over the years, there have been many modifications to the different assessment criteria by combining changes in size and inclusion of metabolic features of specific tumors to overcome the limitations of the traditional criteria [5]. However, these modifications have caused difficulties in assessing treatment efficacy since standardization of response assessments among those clinical trials is lacking. It is critical to distinguish as early as possible between patients who are responding to a particular treatment and those who are not in order to maximize the effectiveness of patient care [5]. In addition, it is important to understand immunotherapy-induced side effects as in some cases treatment might be changed or halted. In this review, we discuss the use of a variety of traditional and new immunotherapy criteria for the evaluation of tumor response in patients who are undergoing immunotherapy. We will also briefly discuss some of the immunotherapy-induced adverse events.

Fig. 7.1
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Cancer imaging in immunotherapy

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7.2 Conventional Imaging Response Criteria (Table 7.1)

Table 7.1 Comparison between the basis of WHO, RECIST 1.0, RECIST 1.1, irRC, and irRECIST criteria [1, 2, 4]
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The WHO and the RECIST criteria were the first criteria developed to assess tumor responses to traditional cancer treatment which included cytotoxic chemotherapy, radiation therapy, or surgical resection. These criteria depend on reduction in tumor size and do not take in consideration appearance of new lesions when evaluating responses that may be related to treatment [4].

7.2.1 WHO Criteria

In 1981, the WHO published the first tumor response criteria thus establishing a standard assessment metric and nomenclature to evaluate treatment response [6]. The WHO criteria introduced the concept of assessing tumor burden using the sum of the products of diameters (SPD) (i.e., longest overall tumor diameter and longest diameter perpendicular to the longest overall diameter) and determining response to therapy by evaluating the changes from baseline during treatment [6]. These criteria were categorized into four tumor response groups: complete response (tumor not detected for at least 4 weeks); partial response (≥50% reduction in the SPD from baseline also confirmed at 4 weeks); progressive disease (≥25% increase in tumor size in one or more lesions); and no change (stable) in disease (neither partial response, complete response, nor progressive disease) (Table 7.1) [7]. However, the WHO has a few major pitfalls (discussed below); in particular, because tumor measurements are based on SPD, small increases in tumor size may result in a sufficiently overall increase in tumor size (≥25% increase) to consider it as progressive disease [5].

7.2.2 RECIST 1.0, 1.1 and mRECIST Criteria

7.2.2.1 RECIST 1.0

In 2000, the RECIST criteria were established and addressed some of the pitfalls of the WHO criteria. Of these, the key features of RECIST included a clear definition of measurable disease, number of lesions to be assessed, and the use of unidimensional (i.e., longest dimension) rather than bidimensional tumor measurements (Table 7.1) [6].

7.2.2.2 RECIST 1.1

In 2009, the RECIST 1.1 were developed. RECIST 1.1 addressed multiple questions regarding the assessment of lymph nodes, number of lesions to be assessed, and use of new imaging modalities such as multidetector CT (MDCT) and magnetic resonance imaging (MRI) [8]. In RECIST 1.1, the number of target lesions is reduced; target lesions can reach a maximum of five lesions (up to two lesions in any one organ) and must be measured in their longest dimension (should be at least 10 mm in longest diameter to be considered measurable), except for lymph nodes which uses the shortest diameter (must be at least 15 mm in the short axis to be considered pathological). In coalescing lesions (non-nodal lesions), its portions should be added together (as lesions coalesce) and measure its longest dimensions [8]. Furthermore, if a lesion cannot be reliably measured, the next largest lesion that can be reproducibly measured should be selected. In addition, if any target lesions (including lymph nodes) become too small to be measured, these should also be recorded and taken in assessment of response and it must be reassessed in follow-up examination to determine if it represents a new lesion [5] (Table 7.1).

7.2.2.3 Modified RECIST (mRECIST)

Modified RECIST (mRECIST) was created to measure the response rate in hepatocellular carcinoma (HCC). Similar to RECIST 1.0 and 1.1, mRECIST uses tumor size as an index of tumor response; however, in contrast, mRECIST takes into account treatment-induced tumor necrosis, and changes in size are determined by assessing for viable tumor, referred to an uptake of contrast agent in the arterial phase on CT or MRI [9, 10]. For example, a complete tumor response is defined as the disappearance of arterial phase enhancement in all target lesions which should be classified as a measurable lesion according to RECIST criteria [5]. Tumors in malignant portal vein thrombosis are considered as nonmeasurable disease since the bland thrombus formed during the course of treatment can obscure the tumor.

7.2.3 Choi Response Criteria

The Choi criteria were initially proposed for assessment of GIST tumors on imatinib, a tyrosine kinase receptor inhibitor. This study found that GISTs on treatment may initially increase in size due to internal hemorrhage, necrosis, or myxoid degeneration. Some may show a minimal decrease in tumor size but not sufficient enough to be classified as having a positive response to therapy according to RECIST criteria [11]. The Choi criteria focuses on changes in density (Hounsfield units on CT) rather than tumor shrinkage to assess response. A decrease in tumor density on CT is often seen in these tumors responding to imatinib and is related to tumor necrosis or myxoid degeneration. There are two main limitations of the Choi criteria; these cannot be applied to MRI and there is lack of sufficient validation in other tumors.

7.2.4 PERCIST Criteria

Based on the premise that newer cancer therapies are more cytostatic than cytocidal, tumor response can manifest with a decrease in metabolism without a notable tumor size reduction [12]. In 2009, the PERCIST criteria were proposed and is based mainly on FDG uptake to evaluate tumor response [13]. PERCIST focuses on the percentage of change in metabolic activity from baseline and the number of weeks from initiation therapy. The standardized uptake value (SUV) corrected for lean body mass (SUL) is used for the assessment of tumor response. The SUL peak is measured within a spherical region of interest of 1.2 cm in diameter (or 1 cm3 for volume) within the area of highest uptake in the tumor [5]. PERCIST defines four metabolic response categories. In brief, according to these criteria, complete response means disappearance of all metabolically active tumors while partial metabolic response is defined as a 0.8-unit (>30%) decline in SUL peak between the most intense lesion before treatment and the most intense lesion after treatment. Of note, the lesion at follow-up may be a different lesion than previously measured since the most active lesion needs to be followed. Progressive disease is defined as an increase (>30%) in SUL peak or the appearance of a new metabolically active lesion [5].

7.3 Immunotherapy Imaging Response Criteria

Evaluating tumor responses during immune therapy in solid cancers remains a challenge [5, 14]. The mechanism of action in immunotherapy differs substantially from cytotoxic agents, thus a well-tailored set of criteria to capture accurate and exact response to this new line of therapeutic agents is needed [4, 5, 14]. To this end, Wolchok et al. presented a set of criteria to evaluate immune-related responses, adopting a bidimensional approach similar to the WHO criteria and measuring a maximum number of five lesions per organ (Table 7.2) [4]. Although these criteria were widely accepted, it still harbors some challenges. For instance, assessing a relatively large number of lesions per organ could be relatively time consuming in cases of extreme tumor burdens [2, 15]. Furthermore, evaluation of excessive number of lesions impacts the reproducibility of the results [2, 15]. As such, Nishino et al. proposed a modification to the immune-related response criteria (irRC) in the light of RECIST 1.1 guidelines [2, 8, 15]. With regard to brain tumors, the Immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria are a set to tumor metrics to assess brain tumors in patients undergoing immune therapies.

Table 7.2 Summary of immune-related response criteria (irRC) [4]
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7.3.1 Immune-Related Response Criteria

Arising from the heightened awareness by the national and international community as to the unique radiographic response patterns seen with vaccines and immunotherapeutics, modifications were made to the WHO and RECIST criteria in 2004 and 2005. In 2009, the immune-related Response Criteria (irRC) published by Wolchok et al. were based on observed patterns in treatment response from phase II clinical trials in advanced melanoma patients who were receiving ipilimumab, a human monoclonal antibody that blocks cytotoxic T lymphocyte antigen–4 (CTLA-4). In this study [4], four patterns of treatment responses were recognized: (1) a decrease in the size of the lesion and without new tumors, similar to what is seen after conventional cytotoxic therapy; (2) stable disease after completion of treatment; (3) a delay in tumor response to therapy after an initial increase in total tumor burden; (4) the appearance of new lesions that precede tumor shrinkage.

In contrast to the WHO and RECIST criteria, irRC takes into account both the index and new measurable lesions to assess the “total tumor burden,” a new concept from prior criteria, and compared to the baseline scan [4]. The irRC was derived from WHO criteria and, therefore, the thresholds of response remain the similar. However, the irRC response categories have been modified from those of WHO criteria [4]. According to the irRC, the sum of the products of the two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five cutaneous index lesions). At every time point, the index lesions and any new measurable lesions are added together to accurately measure the total tumor burden (TTB) [(TTB = SPDindex lesions + SPDnew, measurable lesions)]. This is a major difference from the WHO criteria which considers all new measurable lesions as progressive disease [5]. Further, a confirmatory examination at least 4 weeks from the initial scan documenting progression is required by the irRC prior to declaring progressive disease, as there can be a delay in response in patients on immunotherapy. In addition, decreases in tumor burden must be assessed relative to baseline measurements (i.e., the SPD of all index lesions at screening). The overall response according to the irRC is derived from time-point response assessments based on tumor burden as described in Table 7.2.

The irRC does not mention the use of specific imaging modalities in assessment of tumor response although CT and MRI are typically used. However, research on novel PET radiotracers that incorporate amino acids, nucleotides, choline, and s-receptor to detect the cell proliferation or cell death is being investigated [16]. Further, immune-related adverse effect can be sometimes identified with FDG-PET/CT and metabolic changes can be noted before the clinical symptoms to allow early change of the immunotherapy [1].

7.3.2 Immune-Related RECIST Criteria

The newly proposed irRECIST 1.1 (Table 7.3) and adopted irRC [4] set thresholds for determining different possible responses including complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) [2, 15]. Nishino et al. demonstrated that such changes did not result in any statistically significant variation of the response evaluation in patient with melanoma receiving immunotherapy [2, 15]. They also demonstrated that irRECIST 1.1 measurements were relatively more reproducible than the more involved bidimensional irRC measurements [2, 15]. However, those studies were performed on relatively small cohorts of patients and better evaluation of irRECIST 1.1 is still required.

Table 7.3 Summary of immune-related RECIST 1.1 [2]
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7.3.3 Immunotherapy Response Assessment for Neuro-Oncology Criteria

The iRANO criteria are used to assess brain lesions in patients undergoing immunotherapy [3]. In order that misclassification of patient with stable or increasing tumor size and new lesions as progressive disease does not occur when the therapy is actually effective and the patient is receiving clinical benefit, the iRANO criteria were published. In brief, the iRANO follow the same guidelines as the RANO criteria. However, in those cases of appearance of disease in the absence of clinical deterioration within 6 months of immunotherapy, continuation of immunotherapy and repeat assessment in 3 months is recommended (Table 7.4). As with all current imaging assessment criteria, the iRANO guidelines will require future amendments, including the possible incorporation of volumetrics, advanced imaging sequences, and other types of imaging analytics. A recent study by our group demonstrated that radiomics can discriminate between patients who have pseudoprogression versus true tumor progression with high sensitivity (97%), specificity (79%), and accuracy (95%) in patients with glioblastoma [17].

Table 7.4 Summary of immune therapy Response Assessment in Neuro-Oncology (iRANO) [3]
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7.4 Future Directions for Immune Therapy Imaging Assessment

Although irRECIST and irRC represent an improvement over the conventional WHO criteria and RECIST to evaluate tumor response in immunotherapy, there remains limitations and challenges and further refinements are warranted [4]. Plans for improving imaging response criteria include volumetric (3D) imaging, dynamic contrast imaging, and functional (molecular) imaging. More recently, radiomics is a more recent developing field within imaging that can help in more precise tumor assessments that are un-related to tumor size or burden. Further, radiogenomics, the linkage between imaging phenotypes and tumor genomics, might help develop more robust stratification and end-point imaging biomarkers for molecular targeted clinical trials.

7.5 Immune-Related Adverse Events

Immune-related adverse events (irAE) can represent a serious complication and can be challenging for any imager. Thus, it is important to be aware and take into consideration the possibility of its occurrence so that early management is undertaken [18]. Treatment of adverse events is typically based on published guidelines and includes delaying treatment dosing, administering corticosteroids, or terminating therapy depending on the severity of the event. However, success in outcome lies heavily on correctly identifying and interpreting these complications.

Severe colitis has the highest mortality and worst outcome associated with irAE [18]. Because the possibility of misdiagnosis of autoimmune colitis, the patient can take antibiotic therapy instead of corticosteroid therapy, which can result in a delayed diagnosis and complicated by colonic bowel perforation [18]. Other common immune adverse events are sarcoid-like adenopathy and pancreatitis. It is important to recognize and accurately diagnose these events in order to avoid misdiagnosis as metastatic disease [1]. There are also many other events which can occur with immunotherapy for example autoimmune hepatitis, pneumonitis, thyroiditis, myocarditis, pericarditis, temporal arteritis, conjunctivitis, sarcoid-like reaction such as lymphocytic vasculitis, organizing pneumonia, and fasciitis [19, 20]. Endocrinopathies such as autoimmune hypophysitis and thyroiditis can also be seen. A recent study by our group demonstrated that specific radiomic imaging features were able to predict those patients that will subsequently develop pneumonitis (Fig. 7.2).[21] This study highlights the ability of imaging to identify those patients that might be most susceptible to irAE before the irAE even occurs.

Fig. 7.2
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(a) An illustration of the outlined ROIs in the lungs. An ROI containing three consecutive slices, taken in each lobe in the right lung and ROIs outlined in the left lung correspond to the same level as the right lung ROIs. Post-contrast lung CT images depicting the segmented ROIs in upper (b), middle (c), and lower (d) sections of the right and left lungs. Each ROI is outlined with a different label. Contrast-enhancing vessels from the ROIs were subtracted. Radius of the ROI ranged between 14 and 15 mm

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