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Immunotherapy in Non–Small Cell Lung Cancer Treatment: Current Status and the Role of Imaging

Carter, Brett W. MD*; Halpenny, Darragh F. MD; Ginsberg, Michelle S. MD; Papadimitrakopoulou, Vassiliki A. MD; de Groot, Patricia M. MD*

doi: 10.1097/RTI.0000000000000291
Symposium Review Articles

Lung cancer remains the leading cause of cancer-related mortality and is responsible for more deaths than breast, prostate, and colon cancer combined. Most patients are diagnosed with advanced disease at the time of presentation, and treatment options have traditionally included surgery, chemotherapy, and/or radiation. However, significant advances in the molecular characterization of lung cancer have led to the creation of effective immunotherapies that assist in the recognition of cancer as foreign by the host immune system, stimulate the immune system, and relieve the inhibition that allows tumor growth and spread. Extensive experience with the immunomodulatory monoclonal antibody ipilimumab has demonstrated that unique responses may be seen with immunotherapies that are not adequately captured by traditional response criteria such as the World Health Organization criteria and Response Evaluation Criteria in Solid Tumors (RECIST). Consequently, several modified criteria have been developed to evaluate patients treated with immunotherapy, including immune-related response criteria, immune-related RECIST, and immune RECIST. Finally, patients undergoing immunotherapy may develop a wide variety of immune-related adverse events with which the radiologist must be familiar. In this article, we present the fundamental concepts behind immunotherapy, specific agents currently approved for the treatment of lung cancer, and immune-related adverse events. The role of imaging in the evaluation of these patients will also be discussed, including the general principles of treatment response evaluation, specific response criteria adopted with these agents, including immune-related response criteria, immune-related RECIST, and immune RECIST, and the imaging of immune-related adverse events.

Departments of *Diagnostic Radiology

Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY

The authors declare no conflicts of interest.

Correspondence to: Brett W. Carter, MD, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030 (e-mail: bcarter2@mdanderson.org).

Lung cancer remains the leading cause of cancer-related mortality worldwide and in the United States. Non–small cell lung cancer (NSCLC) and small cell lung cancer are responsible for almost 1 in 4 cancer-related deaths, more than breast, prostate, and colon cancer combined.1 The American Cancer Society estimates that approximately 222,500 new cases of lung cancer (116,990 in men and 105,510 in women) will be diagnosed and 155,870 deaths (84,590 in men and 71,280 in women) will result from lung cancer in 2017.1 Most patients are diagnosed with advanced disease at the time of presentation, and treatment options have traditionally included surgery, chemotherapy, and/or radiation. In the past decade, significant advances in the molecular characterization of lung cancer have resulted in considerable progress in treatment planning and have led to the creation of effective targeted therapies. Nevertheless, in many instances, refractory disease, relapse, and/or spread of disease are experienced by patients.

In contrast to traditional chemotherapy, which mainly targets rapidly dividing cells, and targeted therapies, which interfere with important molecular events in cancer cells that drive growth and invasion, immunotherapy attempts to assist in the recognition of cancer as foreign by the host immune system, stimulate the immune system, and relieve the inhibition that allows tumor growth and spread. Immunotherapy uses both active and passive responses of the immune system to treat many types of cancer. Although immunotherapeutic agents have been approved for several years now to treat such cancers as melanoma and lymphoma, NSCLC was at one time considered nonimmunogenic or not vulnerable to immune-mediated killing of cancer cells, primarily because of failed attempts at immunomodulation with interleukin-2, interferon, and Bacillus Calmette-Guerin.2 However, scientific advances have resulted in the production of immunotherapies that relieve the suppression of antitumor activity in several cancers, including cases of advanced NSCLC. In 2015, nivolumab and pembrolizumab, classified as immunomodulatory monoclonal antibodies, were the first immunotherapeutic agents approved by the US Food and Drug Administration (FDA) for the treatment of advanced NSCLC.3,4

As the treatment options for lung and other cancers continue to advance, development of imaging criteria that can appropriately assess response to therapy is critical. Clinical experience with ipilimumab has demonstrated that several unique responses may be seen with immunotherapies that fail to be adequately captured by traditional response criteria such as the World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST).2 Several response criteria have been developed to evaluate patients treated with immunotherapy, including immune-related response criteria (irRC) and immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).2,5 In addition, patients undergoing immunotherapy may develop a wide variety of immune-related adverse events, some of the most common of which include colitis, hepatitis, pneumonitis, and various endocrine toxicities.6,7 Radiologists must be aware of the imaging findings suggesting the possibility of immune-related adverse events in patients being treated with immunotherapy and distinguish these findings from tumor spread.

In this article, we present the fundamental concepts of immunotherapy, outline specific agents currently approved for the treatment of lung cancer, and discuss immune-related adverse events. The role of imaging in the evaluation of these patients will also be discussed, including the general principles of treatment response evaluation, specific response criteria used with these agents, including irRC, irRECIST, and immune RECIST (iRECIST), and the imaging of immune-related adverse events.

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IMMUNOTHERAPY

General Concepts

Immunotherapeutic approaches to the treatment of cancer are based on the concept that the immune system plays a critical role in antitumor activity. Under normal circumstances, the immune system searches for and identifies abnormal cells and initiates an appropriate response to remove cancer cells after tumor-associated antigens have been identified.8,9 However, cancer cells can avoid detection by the immune system and inhibit antitumor effects, resulting in the continued growth and potential spread of cancer in the body; thus, immunotherapy attempts to boost the immune system and allows it to mount a more effective response.

Immunotherapy has been described as active or passive in nature depending on its interaction with the host immune system and the type of response elicited (Table 1). Active immune response involves humoral and/or cell-mediated immunity. In contrast, passive immune response requires no activation of the immune system, and clearance of tumor cells is stimulated by the binding of passively infused preformed antitumor immunoglobulins to tumor-associated antigens.

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Active Immunotherapy

Active immunotherapy modulates the immune system and has been categorized as nonspecific and specific, the former of which is characterized by a general immune response and the latter of which involves the stimulation of humoral and cell-mediated immunity. Examples of active immunotherapeutic agents include recombinant cytokines, biochemotherapy, cancer vaccines, and immunomodulatory monoclonal antibodies.10

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Recombinant Cytokines and Biochemotherapy

Recombinant cytokines activate the host immune response and have been used for the treatment of several cancers, including melanoma, renal cell carcinoma, lymphoma, chronic myelogenous leukemia, and Kaposi sarcoma. Interleukin-2 and interferon-a have been approved by the FDA.8 These agents act as nonspecific T-cell growth factors, resulting in T-cell proliferation and function, augmentation of natural killer cells, and the release of additional proinflammatory cytokines.10–12

Biochemotherapy is characterized by traditional cytotoxic chemotherapy and recombinant cytokines in concurrent combination, the former of which may be either a single agent or multiple drugs such as dacarbazine, cisplatin, vinblastine, and temozolomide.10,12 This combination can stimulate the immune system because of the active immune response of recombinant cytokines and the cell damage caused by cytotoxic agents, which results in a greater number of tumor antigens available for detection by the immune system. Biochemotherapy has been used in the treatment of melanoma, and although higher response rates than chemotherapy or recombinant cytokines alone have been observed, there is increased toxicity compared with single-agent treatment, and overall survival benefit has not been demonstrated.10

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Cancer Vaccines

Therapeutic cancer vaccines represent an additional type of active immunotherapy. Sipuleucel-T was approved by the FDA in April 2010 for the treatment of metastatic prostate cancer. Other vaccines have been included in clinical trials for cancers such as melanoma, renal cell carcinoma, bladder cancer, glioblastoma, breast cancer, lung cancer, pancreatic cancer, and colon cancer.8,13

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Immunomodulatory Monoclonal Antibodies

Immunomodulatory monoclonal antibodies are a type of active immunotherapy that enhances the immune response through modulation of T-cell activity by interactions with specific cell surface targets such as receptors and/or ligands as part of the cell-mediated adaptive immune response.14,15 The regulation of T-cell activation depends on several factors, including specific receptor-ligand pairs on the cell surface, referred to as immune checkpoints, as well as inhibitor (checkpoint) and costimulatory pathways.16,17 Immunomodulatory monoclonal antibodies may be directed against specific targets such as programmed death protein 1 (PD-1)/programmed death receptor ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and lymphocyte activation gene 3.15,18–23

In March 2011, ipilimumab was approved by the FDA for the treatment of metastatic and unresectable melanoma on the basis of the results of phase III clinical trials demonstrating overall survival benefit.11,15 Ipilimumab is a CTLA-4 checkpoint inhibitor and is a key regulator of immune tolerance. Other immunomodulatory monoclonal antibodies include tremelimumab (another CTLA-4 checkpoint inhibitor), nivolumab, and pembrolizumab, which target PD-1/PD-L1, and atezolizumab, which targets PD-L1.11,16,24 The various response criteria developed for use with immunotherapy as well as adverse effects are primarily based on the radiologic implications of the widespread use of this class of drugs.

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Passive Immunotherapy

Passive immunotherapy requires no activation of the immune system and is characterized by temporary antitumor activity, which is primarily achieved through the utilization of preformed target-specific monoclonal antibodies that bind to tumor-associated antigens and activate clearance of cancer cells by the immune system. Other examples of passive immunotherapy include oncolytic viruses and adoptive T-cell therapy. As these immunotherapeutic agents result in a transient antitumor effect, chronic administration may be necessary. However, it is important to note that cancer cells can develop resistance to these passive agents when the expression of tumor antigens decreases or is lost.

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Target-specific Monoclonal Antibodies

Target-specific monoclonal antibodies inhibit cancer growth through the blockage of receptor sites and inhibition of signaling pathways, through promotion of cancer cell clearance by the immune system via tagging of tumor-associated surface antigens, and through activation of antibody-dependent cell-mediated cytotoxicity.8,9,25 These agents may affect a wide variety of targets. For instance, bevacizumab is a monoclonal antibody that blocks angiogenesis and is directed against vascular endothelial growth factor (VEGF), which has been used to treat glioblastoma multiforme, renal cell carcinoma, and colorectal and lung cancers. Others include trastuzumab, which is directed against human epidermal growth factor receptor 2/neu, and rituximab, which is directed against the CD20 antigen of lymphoma.8,25

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Oncolytic Viruses

Oncolytic viruses constitute a type of passive immunotherapy and are injected locally into tumors and selectively replicate in and kill cancer cells.26 These therapies may be native or engineered and work through tumor debulking following cell lysis and activation of systemic antitumor immunity.27 Tumor-associated antigens are released following cell lysis, resulting in the induction of a sustained cell-mediated antitumor response. The oncolytic virus Talimogene laherparepvec (T-VEC) has been approved by the FDA for the treatment of metastatic melanoma.

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Adoptive T-Cell Therapy

Adoptive T-cell therapy involves the mediation of tumor destruction through the augmentation of T cells, which are harvested from the blood of the patient or the specific tumor. Once these cells are acquired, growth and expansion is promoted through an in vitro culture system, and the cells are then reinfused into the patient.28,29 Some examples of adoptive T-cell therapy currently under investigation include chimeric antigen receptors and tumor-infiltrating lymphocytes.

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IMMUNOTHERAPY FOR LUNG CANCER

Cancer Vaccines

Cancer vaccines are designed to stimulate an immune response to shared or tumor-specific antigens, several of which have been identified on lung cancer cells. These include antigens such as melanoma-associated antigen 3 (MAGE-3), which is found in 42% of lung cancers, NY-ESO-1, an antigen found in normal testis and in various tumors including 30% of lung cancers, p53, a tumor suppressor gene mutated in 50% of lung cancers, survivin, a protein involved in the regulation of apoptosis or programmed cell death, and MUC1, a protein whose expression has been linked to various tumors. A phase I clinical trial of an NY-ESO-1 vaccine that included 10 patients showed that 9 achieved integrated immune responses and 3 patients (2 with lung cancer and 1 with esophageal cancer) had stable disease (SD).30 Several vaccines are currently used in clinical trials involving patients with advanced lung cancer.

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Immunomodulatory Monoclonal Antibodies

Several checkpoint inhibitors have been approved for use in lung cancer therapy. On the basis of the results of several clinical trials, the FDA has approved both nivolumab and pembrolizumab as single agents for the second-line therapy of patients with advanced NSCLC. Nivolumab use does not require testing for PD-L1 expression, whereas pembrolizumab is currently approved for patients with PD-L1 overexpression. In October 2016, pembrolizumab became the first immunotherapeutic drug approved for first-line treatment of patients with metastatic NSCLC whose tumors overexpress PD-L1.

Nivolumab was approved in March 2015 for the treatment of advanced squamous lung cancer refractory to chemotherapy on the basis of the results of several clinical trials. In a phase I expansion trial of nivolumab, 129 patients with advanced disease were treated with 3 different doses of nivolumab (1, 3, or 10 mg/kg) every 2 weeks, and responses were reported in patients with both squamous and nonsquamous NSCLC.31 Median overall survival was 9.9 months, and patients receiving a dose of 3 mg/kg had overall survival rates of 56%, 42%, and 27% at 1, 2, and 3 years, respectively. Two subsequent phase III trials, the CheckMate 017 and CheckMate 057 trials, confirmed the benefit of nivolumab over docetaxel as second-line treatment in patients with advanced NSCLC. In the CheckMate 017 trial, median overall survival was 9.2 months with nivolumab, versus 6.0 months with docetaxel.32 In the CheckMate 057 trial, median overall survival was 12.2 months in patients treated with nivolumab, versus 9.4 months in patients treated with docetaxel. Subgroup analysis from this trial showed higher efficacy for all endpoints in patients with PD-L1-positive tumors.33 The approval of nivolumab was extended to include other types of NSCLC in October 2015 on the basis of the results of these trials.

Pembrolizumab was approved in October 2015 for patients with NSCLC on the basis of the results of a phase I clinical trial. The KEYNOTE-010 trial evaluated the role of pembrolizumab in patients with previously treated advanced NSCLC, and all enrolled patients had at least 1% of tumor cells with PD-L1 expression.34 Patients received either pembrolizumab 2 or 10 mg/kg or docetaxel 75 mg/m2 every 3 weeks. Overall survival was improved with both doses of pembrolizumab (10.4 mo for 2 mg/kg and 12.7 mo for 10 mg/kg) compared with that observed with the administration of docetaxel. In patients with at least 50% of tumor cells expressing PD-L1, survival was higher for pembrolizumab (14.9 mo with 2 mg/kg and 17.3 mo with 10 mg/kg), versus 8.2 months with docetaxel.34

Atezolizumab, an anti-PD-L1 agent, was approved in October 2016 for the treatment of metastatic NSCLC that has progressed during or after first-line platinum-based chemotherapy. For patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, it is indicated for use after the patient’s disease has progressed with an FDA-approved targeted therapy. The approval of atezolizumab was based on the findings from the OAK and POPLAR clinical trials. In the OAK study, patients who received atezolizumab had a median overall survival of 13.8 months, versus 9.6 months for those treated with docetaxel.35 In the POPLAR trial, median overall survival was 12.6 months for atezolizumab versus 9.7 months for docetaxel.36

Other checkpoint inhibitors are currently under investigation, as are combination checkpoint inhibitor approaches, including clinical trials involving combinations of nivolumab and ipilimumab, and durvalumab and tremelimumab.

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Target-specific Monoclonal Antibodies

Several target-specific monoclonal antibodies have been approved for the treatment of patients with lung cancer, including bevacizumab and ramucirumab. Bevacizumab, which blocks angiogenesis and is directed against VEGF, is administered in combination with carboplatin and paclitaxel for the initial systemic treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous cell NSCLC. Ramucirumab, which is directed against the VEGFR2, is approved for use with docetaxel to treat patients with metastatic NSCLC whose disease has progressed after treatment with standard chemotherapy. Patients with NSCLC and EGFR and/or ALK aberrations may also receive ramucirumab once progression has occurred with FDA-approved therapy for these mutations.

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ROLE OF IMAGING IN THE EVALUATION OF TREATMENT RESPONSE

General Principles

Investigators have traditionally relied on response criteria to evaluate the effectiveness of chemotherapy, the most widely used of which are the WHO and RECIST criteria. The WHO criteria were the first widely used guidelines but were hampered by several limitations.37 RECIST 1.0, published in 2000, was developed by a large, international group of investigators to standardize the characterization of treatment efficacy using specific response definitions.38 This was followed by the release of revised RECIST criteria (RECIST 1.1) in 2009.39 These response criteria are optimized to evaluate the cytotoxic effects of chemotherapeutic agents on tumors, and specific recognizable and measurable effects can be identified on imaging studies within a few weeks of therapy. These guidelines assume that an increase in tumor growth and/or the appearance of new lesions indicate progressive disease (PD) in patients treated with cytotoxic agents, which are typically discontinued once PD has been reached.

However, one of the most significant limitations of WHO and RECIST is that several specific patterns of response known to occur in patients treated with immunotherapy are not appropriately captured. In 2004 and 2005, a large multidisciplinary group of experts including oncologists, immunotherapists, and regulatory experts discussed their experiences with treatment response evaluation in the context of immunotherapy and identified several key points: (1) the appearance of measurable antitumor activity may take longer for immunotherapeutic agents than for traditional cytotoxic chemotherapy; (2) treatment responses to immunotherapy may occur after identification of PD by conventional response criteria; (3) discontinuation of immunotherapeutic agents may not be appropriate unless PD is confirmed; (4) allowance for “clinically insignificant” PD is recommended (eg, the appearance of new small lesions in a patient with other lesions that are responding to therapy); and (5) prolonged and durable SD may represent effective antitumor activity.2 On the basis of these observations, experts recommended that existing response criteria be modified in order to address these issues, and irRC was created from the backbone of WHO.

An analysis of 487 patients with advanced (unresectable stage III or IV) melanoma treated with ipilimumab in 3 multicenter phase II clinical trials demonstrated 4 patterns of clinical responses. These patients were treated with induction therapy (10 mg/kg every 3 wk×4) followed by maintenance therapy in certain eligible patients (10 mg/kg every 12 wk, beginning at week 24), and treatment responses were evaluated using WHO criteria and irRC beginning at week 12. Two of the response patterns were appropriately captured with conventional response criteria, including response in baseline lesions evident by week 12 (and no new lesions), and SD, which in some patients was followed by a slow, steady decline in disease. The other 2 response patterns were novel and included responses after an initial increase in total tumor burden (so-called pseudoprogression) and a reduction in total tumor burden during or after the appearance of new lesion(s) at time points later than week 12.2

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irRC

General Principles

irRC is a novel set of response criteria adapted from the WHO criteria designed to specifically address appropriate imaging follow-up recommendations for patients treated with immunotherapy. irRC differs from response criteria such as RECIST in several distinct ways (Table 2). In addition, it is recommended that response assessment after the completion of treatment be made with 2 consecutive follow-up imaging studies at least 4 weeks apart because of a potentially delayed response to therapy. Furthermore, new or enlarging lesions are not necessarily considered PD and must be confirmed with follow-up imaging.

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Application

irRC does not specifically address which imaging modalities should be used in the evaluation of treatment response, and anatomic (computed tomography [CT]) and combined anatomic and metabolic (FDG PET/CT) modalities are often used interchangeably in clinical trials. However, it should be noted that only anatomic measurements are considered in irRC for the evaluation of treatment response. For all cases, tumor burden, consisting of the sum of the products of the 2 largest perpendicular diameters [sum of the products of diameters (SPD)] of all index lesions (measured in mm2), is calculated at baseline and at all subsequent time points. Index lesions must measure ≥5×5 mm, and up to 5 may be selected per organ (up to 10 visceral lesions and 5 cutaneous lesions). At subsequent time points, the tumor burden is calculated by the addition of the SPD of all index lesions and the SPD of any new measurable lesions.

Similar to other response criteria, an overall response category is assigned to each case on the basis of the tumor burden change between time-point assessments. These responses include irCR, irPR, irSD, and irPD (Table 3). As previously stated, new lesions are not automatically considered PD. Overall tumor burden must increase ≥25% and be confirmed by repeat imaging not earlier than 4 weeks later to constitute PD, as new lesions or a perceived increase in tumor burden due to pseudoprogression can result from immune cell recruitment to sites of microscopic disease (Figs. 1, 2). In fact, all patients with irCR, irPR, and irPD must undergo repeat imaging at a minimum of 4 weeks later for confirmation. Patients with irSD, particularly those with slow-declining tumor burden ≥25% from baseline at the last tumor assessment, are considered clinically meaningful because they show an objectively measurable reduction in tumor burden without reaching the 50% threshold that defines irPR.

It should be noted that the FDA has not yet approved irRC as primary tumor response criteria. However, it has been used in several clinical trials alongside traditional response criteria in which the patient continues therapy beyond initial systemic PD by RECIST 1.1 criteria, provided there is investigator-assessed clinical benefit and the patient adequately tolerates the study drug. Implementation of the irRC is useful to avoid premature termination of effective immunotherapeutic treatments when evaluating treatment response with currently available imaging tools in clinical practice. For instance, Hodi and colleagues compared irRC and RECIST in patients with advanced melanoma receiving pembrolizumab, and they discovered that RECIST underestimated the therapy benefit (on the basis of overall survival) in approximately 15% of patients and suggested that the use of modified criteria that permit treatment beyond initial progression per RECIST version 1.1 might prevent premature cessation of treatment.40 It should be noted that, in contrast to other response criteria, nontarget lesions do not contribute to PD but can preclude CR.

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irRECIST

General Principles

Nishino and colleagues evaluated the impact of reducing the number of target lesions and utilizing unidimensional measurements in assessing the treatment response of patients with advanced melanoma treated with ipilimumab. It was discovered that using unidimensional measurements (simulating RECIST 1.1) provided a highly concordant response assessment compared with that obtained with the bidimensional irRC, with less measurement variability.5 The group concluded that the number of target lesions in immune-related response assessment could be reduced to up to 2 per organ and up to 5 in total as defined in RECIST 1.1 and proposed the utilization of unidimensional measurements to assess response to immunotherapy in solid tumors given its relative simplicity, higher reproducibility, and high concordance with the bidimensional measurements of irRC.5

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Application

The application of irRECIST is very similar to that of RECIST 1.1 in terms of recommended imaging modalities, definitions of measureable and unmeasurable disease, and criteria for selecting target and nontarget lesions. For instance, target lesions may include non–lymph-node lesions measuring ≥10 mm in long-axis diameter or lymph nodes measuring ≥15 mm in short-axis diameter. As in RECIST 1.1, up to 5 total target lesions may be selected with a maximum of 2 per organ, and the measurements of these lesions are recorded as the total measured tumor burden (TMTB). Nontarget lesions may include measurable lesions not selected as target lesions, sites of nonmeasurable disease, and lesions that may be difficult to reproducibly measure, such as bone metastases, leptomeningeal metastases, inflammatory breast disease, malignant ascites, pleural or pericardial effusions, lymphangitic carcinomatosis, and cystic lesions. In general, lesions that have been previously treated should not be selected as target lesions unless there has been a demonstration of local progression.

One of the greatest differences between irRECIST, RECIST 1.1, and irRC is the method by which new lesions are incorporated into the response assessment. In irRECIST, new lesions may be designated as measurable or unmeasurable, and those selected as new target lesions must meet the same criteria for inclusion as baseline lesions. It is recommended that such lesions be prioritized according to size, with the largest lesions selected as new target lesions. A total of 5 new target lesions may be selected with a maximum of 2 per organ. New measurable lesions not selected as target lesions may be considered new nonmeasurable lesions and can be followed up qualitatively. When new target lesions are present, the longest diameters of existing non-nodal target and new non–lymph-node target lesions, and short-axis diameters of existing lymph node target and new lymph node target lesions constitute the TMTB. In contrast, once new lesions are identified using RECIST 1.1, the overall response is considered PD, and therapy is typically discontinued, without a method of following up these new lesions.

The overall response categories for irRECIST include irCR, irSD, irPR, and irPD and are based on the TMTB of measured target lesions (baseline and new), nontarget lesion assessment, and new nonmeasurable lesions (Table 4). The specific thresholds for irPR and irPD are aligned with RECIST 1.1, and confirmation with repeat scanning is not necessary. However, for patients with irPD, confirmatory evaluation may be recommended for patients with a minimal TMTB percent increase over 20%, particularly during the first 12 weeks of treatment.

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iRECIST

General Principles

A limitation of irRECIST is the fact that these recommendations have not always been consistently applied, raising concerns among clinicians and researchers regarding the comparability of data and results across various trials. The RECIST working group has recently developed and published guidelines for the use of a modified RECIST 1.1 algorithm to ensure consistent design and data collection termed iRECIST.41 It should be noted that these response criteria are designed to provide a consistent framework for the management of data collected in clinical trials in which immunotherapies are used; it is not intended to define or guide clinical practice or treatment decisions.

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Application

The application of iRECIST is very similar to that of RECIST 1.1 and irRECIST in terms of recommended imaging modalities, definitions of measureable and unmeasurable disease, and criteria for selecting target and nontarget lesions.41 New lesions, which may be classified as target or nontarget, are evaluated as in RECIST 1.1 but are recorded separately and not included in the sum of lesions for target lesions identified at baseline.

The overall response categories for iRECIST include iCR, iSD, iPR, unconfirmed progressive disease (iUPD), and confirmed progressive disease (iCPD).41 These responses allow for the identification and improved characterization of atypical responses, such as delayed responses following pseudoprogression. The iUPD category requires confirmation by the increase in lesion size or the number of new lesions in the lesion category in which progression was first identified, or once there has been progression in lesion categories that had not previously met the RECIST 1.1 criteria for progression. If progression is not confirmed, and there is a decrease in tumor burden compared with the baseline study meeting the criteria for iCR, iPR, or iSD, then iUPD must be achieved once again and confirmed at the next time point for iCPD to meet the criteria for iCPD. If there is no change in tumor size or extent, the time-point response remains iUPD. New lesions result in iUPD, but iCPD is achieved only if additional new lesions are present on the subsequent time point or if there is an increase in the size of new lesions (defined as ≥5 mm for the sum of new lesion target or any increase in new lesion nontarget).

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IMMUNE-RELATED ADVERSE EVENTS

General Concepts

Immunotherapy may alter the immune system to the point where unintended autoimmune-mediated complications may develop. Such treatment-related complications are referred to as immune-related adverse events and have been postulated to be the result of either induction of autoimmunity or of a proinflammatory state.42 However, it is important to note that these effects tend to resolve with cessation of therapy, suggesting that these events are not truly autoimmune diseases and are simply due to general immunologic enhancement.6 Although accurate and reliable reporting of adverse events in clinical trials is critical for risk-benefit evaluation of specific immunotherapies, reports reveal substantial variability in the quality of reporting in this regard43,44 and that reporting is typically inadequate.45–47

Dermatologic toxicity is the most common immune-related adverse event and may result in skin rash, which is typically low grade; although toxic necrotizing epidermolysis mucositis has been reported, it is rare.6,7 Other side effects include enterocolitis, hepatitis, pneumonitis, and endocrinopathies such as hypophysitis, thyroiditis, and adrenal insufficiency. Less frequent complications include sarcoid-like reaction, acute kidney injury, pancreatitis, neurotoxicity, cardiotoxicity, and ophthalmologic toxicity. 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.48 Opportunistic infection may occur in the context of immunosuppressive therapy used to ameliorate the side effects in patients undergoing immunomodulatory therapy, and the reported cases include Aspergillus fumigatus pneumonia, cytomegalovirus viremia, and Fournier’s gangrene.49

Immune-related adverse events can occur with a wide variety of immunotherapeutic agents, but the greatest experience thus far has been with ipilimumab. These events can occur early in the course of therapy, even after the first treatment. This is reflected in the fact that most immune-related adverse events associated with ipilimumab occurred during the 12-week induction period.50,51 The median onset of dermatologic toxicity was 3 weeks, hepatitis occurred at 3 to 9 weeks, enterocolitis occurred at 8 weeks, and endocrinopathy-related events occurred between 7 and 20 weeks.51 Early experience with anti-PD-1 antibodies suggests a lower likelihood of developing immune-related adverse events compared with that observed with the use of ipilimumab. Other work has demonstrated that adverse events may be more common in patients receiving combination immunotherapy. For instance, Naidoo and colleagues found that patients with solid malignancies treated with anti-PD-1/PD-L1 monoclonal antibodies in combination with anti-CTLA-4 monoclonal antibodies were more likely than those treated with a PD-1/PD-L1 inhibitor alone to develop pneumonitis, with an incidence of 10% compared with 3%.52

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Risk Factors and Management

Immunomodulatory monoclonal antibody therapy is not recommended for patients with preexisting autoimmune diseases, especially inflammatory bowel disease and autoimmune hepatitis, or with chronic infections such as HIV or Hepatitis B or C.6,7 It was observed in an early clinical study with ipilimumab that a positive correlation existed between response to therapy and development of immune-related adverse events.50 Adverse events related to immunotherapy are treated on the basis of observed toxicity. Patients are typically responsive to interruption or discontinuation of therapy with or without the addition of immunosuppressive medications, some of which include corticosteroids or tumor necrosis factor-alpha antagonists.51

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IMAGING OF IMMUNE-RELATED ADVERSE EVENTS

Radiologists must be able to recognize the unique adverse events associated with immunotherapy to guide appropriate management and prevent misinterpretation. Findings consistent with adverse events may be identified on CT or PET/CT performed for restaging and/or surveillance purposes. PET/CT may be especially beneficial as immune-related adverse events may be detected earlier with this modality and can precede clinical symptoms, allowing early therapeutic interventions. Several of the most common adverse events that may be encountered by radiologists will be described herein.

In the thorax, pneumonitis is the most common immune-related adverse event. Although chest radiography may be the first imaging modality to demonstrate abnormalities attributable to pneumonitis, Naidoo et al52 showed that only 67% of cases resulted in identifiable findings. In this study, several different patterns of disease were identified, including (1) cryptogenic organizing pneumonia-like, (2) ground-glass opacities, (3) interstitial pattern, (4) hypersensitivity pneumonitis-like, and (5) pneumonitis not otherwise specified (Figs. 3, 4). A few of the cases in this study demonstrated evolution, such as cryptogenic organizing pneumonia–like pneumonitis patients developing extensive ground-glass opacities and others with a ground-glass pattern later showing interstitial abnormalities. Nodular pneumonitis is an important potential pitfall of which radiologists should be aware in that it may mimic recurrent disease radiologically.

Sarcoid-like reaction is a rare complication that can manifest with multiple micronodules with or without ground-glass opacities and/or mediastinal/hilar lymphadenopathy53 (Fig. 5). Cardiovascular abnormalities include pericarditis, which may result in pericardial effusion and/or pericardial thickening on CT (Fig. 6). Echocardiography and magnetic resonance imaging may demonstrate septal bounce and respiratory septal shift, suggesting ventricular interdependence and constrictive effusive physiology.54–56 Thyroid disease associated with immunotherapy typically results in thyroiditis, which may manifest on iodine-123 thyroid scintigraphy and/or ultrasound. On CT, thyroiditis typically results in enlargement and hypoattenuation of the thyroid gland (Fig. 7). Given the increasing utilization of FDG PET/CT to evaluate patients, immune-related thyroiditis may be identified as diffusely increased FDG uptake on PET/CT (Fig. 8). Tracheitis is an uncommon intrathoracic complication of immunotherapy that may be encountered (Fig. 9).

In the abdomen and/or pelvis, several adverse effects may be identified, the most common of which include colitis and hepatitis. Colitis is a significant complication that is associated with the highest mortality of all immune-related adverse events. Prolonged time between diagnosis and management of colitis is associated with poor outcomes; therefore, prompt diagnosis and intervention is necessary.57 The findings of immune-related colitis are well described and include wall thickening (which may be segmental or diffuse), mucosal enhancement, submucosal edema, air-fluid levels, infiltration of the pericolonic fat, and ascites. There are 2 different patterns associated with ipilimumab treatment: diffuse colitis, manifesting clinically as watery diarrhea, and segmental colitis in the setting of diverticulosis, manifesting clinically as watery or bloody diarrhea58 (Fig. 10). The diffuse form is usually treated with corticosteroids, whereas the segmental form is treated with both corticosteroids and antibiotics. Autoimmune hepatitis may be detected on ultrasound and/or CT, resulting in periportal or portal vein hyperechogenicity on the former and periportal edema and hypoattenuation of the edematous liver parenchyma on the latter.58,59 These imaging findings are not specific for autoimmune hepatitis, but the imager should recognize the possibility of autoimmune hepatitis in the setting of cancer immunotherapy. The CT findings of autoimmune pancreatitis are similar to those of acute pancreatitis unrelated to immunotherapy and include enlargement and an edematous appearance of the pancreas with adjacent fat stranding, edema, and free fluid60 (Fig. 11). On FDG PET/CT, diffusely increased FDG uptake may be present throughout the body of the pancreas.61

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CONCLUSIONS

The role of immunotherapy in treating patients continues to expand, and a basic understanding of the mechanisms underlying its efficacy is essential. As radiologists become more involved in the care of these patients through the interpretation of staging and restaging examinations, an understanding of the modified response criteria used to evaluate these patients, such as irRC, irRECIST, and iRECIST, is essential to guide appropriate management. Finally, a wide variety of immune-related adverse events may affect patients treated with immunotherapy, and the radiologist plays an important role in the prompt identification and reporting of such side effects.

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Keywords:

lung cancer; immunotherapy; computed tomography; F-18 fluoro-deoxy-glucose positron emission tomography/computed tomography

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