Imaging Findings of Complications of New Anticancer Drugs

Abstract

The anticancer drugs have evolved significantly, spanning molecular targeted therapeutics (MTTs), immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell (CAR-T) therapy, and antibody-drug conjugates (ADCs). Complications associated with these drugs vary widely based on their mechanisms of action. MTTs that target angiogenesis can often lead to complications related to ischemia or endothelial damage across various organs, whereas non-anti-angiogenic MTTs present unique complications derived from their specific pharmacological actions. ICIs are predominantly associated with immune-related adverse events, such as pneumonitis, colitis, hepatitis, thyroid disorders, hypophysitis, and sarcoid-like reactions. CAR-T therapy causes unique and severe complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. ADCs tend to cause complications associated with cytotoxic payloads. A comprehensive understanding of these drug-specific toxicities, particularly using medical imaging, is essential for providing optimal patient care. Based on this knowledge, radiologists can play a pivotal role in multidisciplinary teams. Therefore, radiologists must stay up-to-date on the imaging characteristics of these complications and the mechanisms underlying novel anticancer drugs.

INTRODUCTION

Over the past few decades, cancer treatment has advanced significantly, with the development of anticancer drugs targeting various mechanisms and the widespread use of drug combinations in clinical practice. Additionally, trends in anticancer drug development have shifted from molecular targeted agents and immunotherapy to cell therapies and antibody derivatives. Precision medicine in oncology refers to a cancer treatment approach specifically tailored to individual patients by utilizing their unique genetic and molecular or immunological profiles [1].

With the emergence of novel immunotherapies and continuous progress in precision medicine, medical imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) play crucial roles in the prompt and precise evaluation of treatment responses and complications (also known as toxicities, adverse events, or adverse drug reactions). Patterns of treatment response and complications can vary according to the specific therapeutic agents administered. Therefore, meticulous evaluation of both the therapeutic effects and toxicities is imperative based on the type of therapeutic agent [2].

Imaging assessment of therapeutic effects has been established over the past three decades using various treatment response criteria such as the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for solid tumors, the Lugano staging classification for lymphoma, and the Response Assessment in Neuro-Oncology (RANO) criteria 2.0 for glioblastoma [2]. In contrast, imaging assessments for complications of therapeutic agents have been less explored compared to those for therapeutic effects. Radiologists often possess limited comprehensive insights into toxicities resulting from the mechanisms of new anticancer drugs [3].

Therefore, we aimed to review the major complications associated with the development of new anticancer drugs and to provide drug-specific imaging patterns based on their mechanisms of action.

Trends in Anticancer Drug Development

Anticancer drugs can generally be classified into several categories based on their mechanism of action, as follows: cytotoxic chemotherapeutic agents, molecular targeted therapeutics (MTTs), immunotherapy, cell and gene therapy (CGT), hormonal therapy, and others, as summarized in Table 1. In the 2000s, MTTs were predominantly used, whereas in the 2010s, immunotherapy, particularly immune checkpoint inhibitors (ICIs), emerged as the mainstream treatment for various types of cancer [2]. In the 2020s, CGTs such as chimeric antigen receptor T-cell (CAR-T) and antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (Enhertu^®) are gaining momentum (Fig. 1). Advancements in new anticancer drugs with distinct mechanisms have significantly improved the survival rates of patients with cancer. However, these advancements come with potential complications, including multi-organ toxicities with distinct profiles, which may impose an additional burden on healthcare providers [4].

Table 1. Common classification of anticancer drugs.

Classification	Mechanism of action	Examples
Cytotoxic chemotherapeutic agents	Directly damage DNA of cancer cells, inhibit DNA synthesis, disrupt cell division	Cyclophosphamide, cisplatin, methotrexate
Molecular targeted therapeutics	Target specific molecules or pathways involved in cancer growth and survival	Imatinib, trastuzumab, pembrolizumab
Immunotherapy	Enhance the body’s immune response to recognize and destroy cancer cells	ICIs (pembrolizumab, nivolumab), IL-2
Cell and gene therapy	Introduce genetic material or modify cells to target and destroy cancer cells	CAR-T therapy, oncolytic viruses
Hormonal therapy	Block the production or action of hormones that fuel cancer growth	Tamoxifen, aromatase inhibitors, androgen receptor antagonists
Antibody-drug conjugates	Antibodies target specific antigens on cancer cells, delivering cytotoxic drugs	Ado-trastuzumab emtansine (Kadcyla), trastuzumab deruxtecan (Enhertu)

DNA = deoxyribonucleic acid, ICI = immune checkpoint inhibitor, IL = interleukin, CAR-T = chimeric antigen receptor T-cell therapy

Fig. 1. Evolution of novel anticancer drugs. CAR-T = chimeric antigen receptor T-cell.

Roles of Radiologists in Complication Evaluation

Evaluating complications associated with new anticancer drugs is crucial for optimal patient care, with imaging playing a pivotal role in the detection, characterization, and monitoring of adverse effects [5]. Here, we outline the role of radiologists in evaluating complications in patients with cancer treated with new anticancer drugs [4,6]. Radiologists, in collaboration with oncologists, pulmonologists, neurologists, and other specialists, should adopt a multidisciplinary approach that integrates both imaging and clinical information to optimize the care of these patients treated with new anticancer drugs.

Detection

If radiologists detect early signs of drug-induced toxicity on imaging before clinical symptoms appear, they can facilitate timely intervention by clinicians, potentially reducing the severity of complications and enhancing patient outcomes. For example, radiologists should carefully evaluate CT scans for signs of interstitial pneumonitis in patients treated with various MTTs, ICIs, or ADCs, enabling early management with steroids or watchful observation [7].

Screening/Surveillance

For anticancer drugs known for their potential cardiac toxicity, such as human epidermal growth factor receptor 2 (HER2) inhibitors or anti-angiogenic agents, international guidelines, such as the European Society for Medical Oncology guidelines, recommend regular surveillance with echocardiography or cardiac MRI [8].

Characterization

Radiologists can provide detailed information on the nature and extent of organ damage or dysfunction induced by anticancer medications. For example, liver MRI or FibroScan (transient elastography) using ultrasonography can be used to assess drug-induced hepatosteatosis in patients undergoing treatment with lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, revealing hyperlipidemia. This information enables timely intervention with lipid-lowering agents or consideration of alternate options [7].

Monitoring

Through serial imaging, radiologists can monitor the progression of drug-induced complications and assess the efficacy of the current management strategies. Imaging information, such as changes in the severity or extent of complications over time, can assist clinicians in making informed decisions about whether to continue, modify, or discontinue anticancer drugs, as well as determine the appropriate treatment for complications [7].

Supporting Research

In clinical trials and drug development, imaging plays a vital role in assessing the safety profile of new anticancer agents. It helps in understanding the mechanisms of drug toxicity and developing strategies to reduce adverse effects [9].

Complications of Molecular Targeted Therapeutics

MTT assays are typically categorized as small-molecule drugs or monoclonal antibodies. Based on their molecular targets in various pathways involved in cancer cell growth, small-molecule drugs can be categorized into several classes, including ALK inhibitors, BCR-ABL inhibitors, B-Raf inhibitors, BTK inhibitors, EGFR inhibitors, HER2 inhibitors, NTRK inhibitors, VEGFR inhibitors, and mTOR inhibitors (Table 2). Monoclonal antibodies, classified based on their specific antigens on cancer cell surface or in the blood vessels, include trastuzumab (Herceptin^®) targeting the HER2/neu receptor in breast cancer, rituximab (Rituxan^®), aimed at the CD20 antigen in B-cell non-Hodgkin lymphoma, and bevacizumab (Avastin^®) targeting circulating vascular endothelial growth factor (VEGF) in blood vessels [7].

Table 2. Classification of small molecule MTTs and common complications visible on imaging.

Category	Common drugs	Common complications visible on imaging
ALK inhibitors	Crizotinib, Ceritinib, Alectinib, Lorlatinib	Renal cysts and abscesses Hepatosteatosis
BCR-ABL inhibitors	Imatinib, Dasatinib, Nilotinib	Fluid retention, pleuropericardial effusion, enterocolitis, pancreatitis
B-Raf inhibitors	Vemurafenib, Dabrafenib	Pancreatitis, pericardial effusion
BTK inhibitors	Ibrutinib, Acalabrutinib	GI bleeding, intracranial hemorrhage
EGFR inhibitors	Gefitinib, Erlotinib, Afatinib	Interstitial pneumonitis
HER2 inhibitors	Neratinib, Tucatinib	Congestive heart failure with decreased LVEF
NTRK inhibitors	Larotrectinib, Entrectinib	Weight gain with increased adipose tissue
VEGFR inhibitors	Sorafenib, Sunitinib, Lenvatinib, Cabozantinib	Ischemic colitis, pneumatosis intestinalis, bowel perforation, anastomosis dehiscence, cholecystitis, pancreatitis, thromboembolism, cardiomyopathy
mTOR inhibitors	Everolimus, Temsirolimus	Interstitial pneumonitis, cholecystitis, pancreatitis, thromboembolism

MTT = molecular targeted therapeutics, ALK = anaplastic lymphoma kinase, BCR-ABL = breakpoint cluster region-Abelson, B-Raf = v-Raf murine sarcoma viral oncogene homolog B, BTK = Bruton’s tyrosine kinase, GI = gastrointestinal, EGFR = epidermal growth factor receptor, HER2 = human epidermal growth factor receptor 2, LVEF = left ventricular ejection fraction, NTRK = neurotrophic tyrosine receptor kinase, VEGFR = vascular endothelial growth factor receptor, mTOR = mammalian target of rapamycin

Drugs targeting the VEGF and its receptor (VEGFR) pathways are classified as anti-angiogenic agents. This group includes VEGFR-targeted tyrosine kinase inhibitors (TKIs), such as lenvatinib, cabozantinib, and sunitinib, as well as bevacizumab, which directly targets circulating VEGF. Multi-targeted TKIs, such as sorafenib, are also considered anti-angiogenic agents when they inhibit the VEGFR pathway. Conversely, drugs that do not target these pathways are considered non-anti-angiogenic agents, focusing on alternative mechanisms [10]. From an imaging perspective, distinguishing between anti-angiogenic and non-anti-angiogenic agents is important because anti-angiogenic agents exhibit toxicities specifically related to the VEGF or VEGFR pathways [11,12].

Complications from anti-angiogenic drugs targeting VEGF or VEGFR primarily affect normal angiogenesis, leading to endothelial injury or ischemia in various organs. Complications such as ischemic colitis, pneumatosis intestinalis, and bowel perforation may occur as a result of bowel ischemia. Impaired wound healing or anastomotic dehiscence can occur postoperatively (Fig. 2). Although less frequent, gallbladder and pancreatic ischemia can lead to gangrenous cholecystitis and pancreatitis, respectively. Furthermore, these drugs can induce arterial and venous thromboembolic events due to endothelial damage [10].

Fig. 2. A 59-year-old male treated with low anterior resection and chemotherapy (FOLFOX + bevacizumab) for rectal cancer. Abdominal CT demonstrates an anastomosis dehiscence (thin arrow) and adjacent free air pockets (thick arrows).

Complications associated with non-anti-angiogenic drugs are primarily due to their pharmacological effects on normal cells, known as on-target toxicities. However, some complications arise from off-target toxicities unrelated to the intended action of the drug. Only a subset of these complications could be visualized using imaging (Table 2) [11]. Interstitial pneumonitis is a common, radiologically evident toxicity associated with the use of EGFR, mTOR, and ALK inhibitors (Fig. 3). The incidence rates of interstitial pneumonitis are 1.1% for EGFR inhibitors and 2.1% for ALK inhibitors [13,14]. However, these rates are notably higher in the Japanese population, reaching up to 4.77%, indicating a potential ethnic predisposition that influences the risk of developing this complication during treatment [13,14]. Fluid retention, including subcutaneous edema, ascites, pleural effusion, and pericardial effusion, is a common complication associated with imatinib use in patients with gastrointestinal (GI) stromal tumors [15]. Imaging plays a crucial role in assessing the severity of fluid retention, thereby facilitating personalized management strategies for affected patients (Fig. 4) [16]. Dasatinib is frequently associated with pleuro-pericardial effusion.

Fig. 3. A 61-year-old female treated with temsilolimus for metastatic renal cell carcinoma. Six months after starting temsilolimus, chest CT demonstrates multifocal, predominantly peripheral ground-glass opacites in both lower lobes of the lungs, indicative of drug-related interstitial pneumonitis in a nonspecific interstitial pneumonitis patten. The patient reported a persistent mild cough over several months without clinical signs of infection that subsequently improved.

Fig. 4. A 55-year-old male patients treated with imatinib for gastrointestinal stromal tumor. A: On initial CT prior to the imatinib treatment, There are liver metastasis (thin arrow) and peritoneal seeding (thick arrow). B: On follow-up CT after starting imatinib treatment, the liver metastasis shows cystic degeneration (thin arrow) with a significant reduction in tumor density by more than 15%, consistent with a partial response per the Choi criteria. Notably, the peritoneal seeding (thick arrow) is almost resolved. Moderate amount of ascites is also observed, indicating imatinib-associated fluid retention.

Complications of Immunotherapy

The term “immunotherapy” encompasses a broad range of treatments, such as ICIs, cytokine therapy, cancer vaccines, and CAR-T cell therapy. Here, we focused on ICIs, which are currently regarded as the mainstay of immunotherapy and are known to enhance T-cell activity against immune-evasive tumors [17]. The main targets of ICIs are PD-1 on T-cells and its ligand PD-L1 on tumor cells, which regulate peripheral T-cell activity, and CTLA-4 on T-cells, which affects the activation of naive and memory T-cells [1]. The targets and indications for ICIs are summarized in Table 3. ICIs can lead to unique response patterns such as pseudoprogression and are associated with specific autoimmune-like side effects, termed immune-related adverse events (irAEs) [18,19].

Table 3. Indications and complications of immune checkpoint inhibitors.

Drug	Target	Indications	irAEs visible on imaging*
Ipilimumab	CTLA-4	Melanoma, RCC, CRC, HNSCC, NSCLC, MPM, EC	Pneumonitis, colitis, hepatitis, thyroid disorders, hypophysitis, pancreatitis, sarcoid-like reaction, and myositis
Pembrolizumab	PD-1	Melanoma, HNSCC, cHL, PMBCL, UC, CRC, GC, EC, MCC, RCC, cSCC, TNBC
Nivolumab	PD-1	Melanoma, NSCLC, MPM, RCC, cHL, HNSCC, UC, CRC, HCC, EC, GC, GJC, EAC
Atezolizumab	PD-L1	UC, NSCLC, ES-SCLC, HCC, melanoma
Avelumab	PD-L1	MCC, UC, RCC
Durvalumab	PD-L1	UC, NSCLC, SCLC, BTC
Cemiplimab	PD-1	cSCC, BCC, NSCLC

^*irAEs are common across all immune checkpoint inhibitors.

irAEs = immune related adverse events, RCC = renal cell carcinoma, CRC = colorectal cancer, HNSCC = head and neck squamous cell cancer, NSCLC = non-small cell lung cancer, MPM = malignant pleural mesothelioma, EC = esophageal cancer, cHL = Classical Hodgkin lymphoma, PMBCL = primary mediastinal large B-cell lymphoma, UC = urothelial carcinoma, GC = gastric cancer, MCC = Merkel cell carcinoma, cSCC = cutaneous squamous cell carcinoma, TNBC = triple-negative breast cancer, HCC = hepatocellular carcinoma, GJC = gastroesophageal junction cancer, EAC = esophageal adenocarcinoma, ES-SCLC = extensive-stage small-cell lung cancer, BTC = biliary tract cancer, BCC = basal cell carcinoma

The mechanisms of irAEs involve the overactivation of the immune system beyond its intended antitumor effects, leading to autoimmunity and inflammation in various organs. By blocking checkpoint pathways, such as PD-1/PD-L1 and CTLA-4, these inhibitors reduce the ability of the immune system to distinguish between healthy and malignant cells, resulting in immune cells attacking normal tissues. These events can affect virtually any organ system but commonly involve the skin (rash, pruritus), GI tract (enteritis, colitis), liver (hepatitis), endocrine system (thyroid disorders, hypophysitis), and lungs (pneumonitis) [1]. Skin irAEs frequently manifest as the initial and most prevalent forms, whereas pneumonitis, colitis, and hepatitis represent more severe complications. The incidence and severity of irAEs vary widely depending on the specific ICI, with CTLA-4 inhibitors typically causing higher rates of irAEs than PD-1 and PD-L1 inhibitors [20].

Pneumonitis is a potentially life-threatening condition and a leading cause of ICI treatment discontinuation [21]. It has been reported that 2.7% of patients receiving ICIs targeting PD-1 develop pneumonitis, and the incidence increases to 4.1% in patients with lung cancer [22]. On chest CT, the radiographic patterns of pneumonitis are classified into nonspecific interstitial pneumonia (NSIP), hypersensitivity pneumonitis (HP), cryptogenic organizing pneumonia (COP), and acute interstitial pneumonia/acute respiratory distress syndrome (AIP/ARDS). Typically, the AIP/ARDS pattern is associated with the most severe symptoms, whereas the COP, NSIP, and HP patterns are indicative of mild to moderate symptoms [23], and the COP pattern is the most frequently observed (Fig. 5). The management of pneumonitis involves the discontinuation of ICI therapy and the initiation of corticosteroids. If pneumonitis resolves, ICI treatment may be resumed, but caution is advised, as there is an approximately 25% chance of recurrence, which poses significant management challenges and may necessitate permanent cessation of ICI therapy [24].

Fig. 5. A 49-year-old female enrolled in a clinical trial of an immune checkpoint inhibitor-based combination therapy for breast cancer. The chest CT scan, taken after starting treatment, demonstrates multifocal parenchymal consolidations with peripheral and lower distribution, indicating pneumonitis of cryptogenic organizing pneumonia pattern.

GI toxicity is the second most common irAE, after dermal toxicity [20]. ICIs can induce a variety of symptoms including diarrhea, abdominal pain, nausea/vomiting, mucus in stools, fecal urgency, and rectal bleeding. Immune-mediated inflammation can manifest in any segment of the GI tract, with colitis being the predominant form of the disease. ICIs disrupt the regulatory mechanisms of the immune system in the GI mucosa, resulting in inflammatory cell infiltration. This ultimately leads to the development of diarrhea and other symptoms associated with colitis [25]. CT findings in ipilimumab-associated colitis include diffuse or segmental bowel wall thickening. The diffuse colitis pattern is characterized by mesenteric vessel engorgement with mild diffuse bowel wall thickening or a fluid-filled distended colon on CT. The segmental colitis pattern is frequently associated with preexisting diverticulosis, characterized by moderate segmental wall thickening and associated pericolic fat stranding within a segment of preexisting diverticulosis (Fig. 6). Treatment involves the cessation of ICIs and the administration of steroids with or without antibiotics, according to clinical manifestations.

Fig. 6. A 63-year-old female enrolled in a clinical trial of an ICI-based combination therapy. A: On the baseline CT scan, diverticulosis is noted in the sigmoid colon without signs of diverticulitis. B: On the follow-up CT scan, taken after starting treatment, segmental enhancing wall thickening occurs in the segment of preexisting diverticulosis, indicating ICI-associated colitis in segmental colitis pattern (thick arrows). She had mild symptoms including mild abdominal pain and frequent loose stool. ICI = immune checkpoint inhibitor.

Hepatic irAEs usually manifest as hepatitis with elevated liver function parameters. The proposed mechanism underlying hepatic irAEs involves the activation of CD8+ T-cells by ICIs, coupled with a lack of regulatory T cell (Treg) activation, leading to immune-related hepatitis [26]. The imaging findings of immune-related hepatitis are identical to those of acute hepatitis, including periportal edema, mild hepatomegaly, and periportal lymphadenopathy [27].

Hypophysitis and thyroid disorders are common endocrine irAEs. Hypophysitis frequently occurs with CTLA-4 inhibitors such as ipilimumab and is rare with PD-1 or PD-L1 inhibitors. Conversely, thyroid disorders have been commonly reported in women treated with PD-1 inhibitors. PET/CT is a useful diagnostic imaging modality, which shows fludeoxyglucose-18 (FDG) uptake in the hypophysis or an enlarged thyroid gland [1]. Endocrine irAEs can be managed with appropriate hormone replacement therapy, enabling patients to continue ICI treatment.

Sarcoid-like reactions are immune responses that occur in normal organs such as the lymph nodes and skin. These reactions are generally asymptomatic but can mimic tumor progression in imaging studies, potentially leading to unnecessary cessation of effective ICI therapy. Common imaging findings of sarcoid-like reactions include bilateral symmetric enlarged lymph nodes in the mediastinal and/or retroperitoneal spaces as well as tiny pulmonary nodules showing a perilymphatic distribution on CT scans. Increased FDG uptake was observed in the affected lymph nodes on PET (Fig. 7) [28]. To avoid misinterpreting sarcoid-like reactions as disease progression according to RECIST 1.1, the response of other target and non-target lesions, beyond the lymph nodes and pulmonary nodules with a perilymphatic distribution, should be assessed. If there is clinical suspicion of a sarcoid-like reaction based on improvement in other target and non-target lesions and the patient’s overall health status, treatment beyond progression (TBP) may be a suitable option. However, there is insufficient evidence to evaluate the duration of sarcoid-like reactions or the impact of discontinuing ICI therapy and initiating steroid treatment.

Fig. 7. An 83-year-old male treated with pembrolizumab and capecitabine. A-C: There are multiple bilateral enlarged lymph nodes (arrows) noted in the mediastinum (A) and retroperitoneum (B) in a symmetric pattern on CT that show increased fluorodeoxyglucose uptake on PET (C). These findings were characterized as sarcoid-like reactions, and the pembrolizumab and capecitabine treatment was continued.

ICI treatment in patients with cancer with preexisting autoimmune diseases can exacerbate inflammation and autoimmunity. For example, underlying diseases, such as psoriasis, autoimmune thyroid diseases, ulcerative colitis, Crohn’s disease, and multiple sclerosis, may worsen during ICI treatment. In some instances, this phenomenon can lead to the development of severe and fatal diseases [29].

Complications of Chimeric Antigen Receptor T Cell Therapy

CAR-T cells are genetically modified T-cells that possess a newly engineered receptor, enabling them to efficiently bind to and kill cancer cells [30]. CAR-T cells are generated by harvesting T-cells from a patient and reengineering them in the laboratory to express proteins on their surface, known as chimeric antigen receptors [31]. Table 4 summarizes the approved CAR-T therapies, including their specific targets, indications, and complications.

Table 4. Indications and complications of CAR-T therapy approved by U.S. FDA.

Drug	Target	Indications	Complications*
Tisagenlecleucel (Kymriah®)	CD19	ALL in pediatric & young adults, R/R large B-cell lymphoma	Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, B-cell aplasia and hypogammaglobulinemia, cytopenias, graft-versus-host disease, tumor lysis syndrome
Axicabtagene ciloleucel (Yescarta®)	CD19	Adults with R/R large B-cell lymphoma
Brexucabtagene autoleucel (Tecartus®)	CD19	Adults with R/R MCL; R/R B-cell precursor ALL
Lisocabtagene maraleucel (Breyanzi®)	CD19	Adults with R/R large B-cell lymphoma
Idecabtagene vicleucel (Abecma®)	BCMA	Adults with R/R multiple myeloma after ≥4 prior lines of therapy
Ciltacabtagene autoleucel (Carvykti®)	BCMA	Adults with R/R multiple myeloma after ≥4 prior lines of therapy

^*Complications are common across all CAR-T therapies.

CAR-T = chimeric antigen receptor T-cell, ALL = acute lymphoblastic leukemia, R/R = relapsed/refractory, MCL = mantle cell lymphoma

Complications of CAR-T include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), B-cell aplasia, hypogammaglobulinemia, cytopenia, and graft-versus-host disease (GvHD). These adverse effects stem from the potent immune response triggered by the infused CAR-T cells [31]. Owing to the potential severity of these complications, patients undergoing CAR-T cell therapy must be closely monitored by a healthcare team experienced in managing these specific toxicities. Early detection and intervention are crucial for risk mitigation.

CRS and ICANS are unique complications of CAR-T cell therapy that require close monitoring and management. CRS is characterized by the rapid release of cytokines into the blood, leading to symptoms ranging from mild flu-like symptoms to severe life-threatening conditions [32]. Imaging findings of CRS are evident on chest CT or radiography. A recent study reported that patients with grade 2 or higher CRS were more likely to develop pleural effusion and atelectasis [32]. Imaging findings of hemodynamic imbalance such as pulmonary edema, pericardial effusion, ascites, and hepatosplenomegaly were also observed.

ICANS is associated with neurological complications that can vary from mild cognitive disturbances to severe encephalopathy and seizures. Although usually negative, brain MRI or CT is recommended in cases of suspected ICANS to assess the presence of edema and rare complications, such as hemorrhage or stroke. On T2-weighted imaging, cerebral edema typically initially involves the thalami and brainstem (Fig. 8). Diffuse cerebral edema may occur in severe cases. Areas of ischemia or cytotoxic edema may show diffusion restriction on diffusion-weighted images. Microhaemorrhages can be observed on susceptibility-weighted images.

Fig. 8. A 41-year-old female treated with CAR-T (Kymriah^®) for follicular lymphoma. A: The initial brain MRI, taken one week after CAR-T administration, demonstrates bilateral symmetric T2 hyperintense lesions in both periventricular white matter and corona radiata on FLAIR sequence, indicating immune effector cell-associated neurotoxicity syndrome. The patient experienced changes in mental status. B: On the follow-up MRI, all T2-hyperintense lesions are resolved. CAR-T = chimeric antigen receptor T-cell, FLAIR = fluid attenuated inversion recovery.

Complications of Antibody-Drug Conjugates

ADCs are designed to deliver cytotoxic drugs directly to cancer cells while sparing healthy cells, thereby reducing the side effects associated with traditional chemotherapy. However, ADCs can cause a range of complications, some of which are common across different ADCs. These complications can arise from the antibody component, cytotoxic payload, or the linker that connects the two. Common complications include myelosuppression, peripheral neuropathy, hepatitis, corneal keratopathy, enterocolitis, interstitial pneumonitis, skin toxicity, and cardiotoxicity, such as heart failure or cardiomyopathy [33].

In contrast to the irAEs of ICIs, which arise from immune reactions, the complications of ADCs are partly due to the chemical toxicity of the cytotoxic payload. For instance, while interstitial pneumonitis associated with ICIs may be an immune-related condition, pneumonitis associated with ADCs may be a form of chemical pneumonitis (Fig. 9). Enterocolitis caused by ADCs is also attributed to the cytotoxic payload affecting cells in the GI tract (Fig. 10). Therefore, imaging findings of these ADC-related complications may resemble those of irAEs; however, they tend to reveal more extensive or severe manifestations of the disease [34].

Fig. 9. A 60-year-old female with urothelial cancer enrolled in a clinical trial of an ADC. A: Chest CT one month after starting ADC treatment shows multifocal consolidations in both lower lobes. The patient presented with a dry cough and shortness of breath. B: Follow-up CT one month after discontinuing ADC treatment shows marked improvement in the consolidations. ADC = antibody-drug conjugate.

Fig. 10. A 56-year-old female with breast cancer enrolled in a clinical trial of an antibody-drug conjugate, presenting with diarrhea and abdominal cramping. A: Coronal abdominal CT image shows a fluid-filled colon without significant bowel wall thickening. B: Axial abdominal CT image also shows a fluid-filled colon with mild gaseous distension.

Onset Time of Common Complications of Immunotherapy and CAR-T Therapy

Understanding the typical onset time of the complications of immunotherapy and CAR-T therapy is crucial for radiologists when interpreting CT and MRI findings. Radiologists should be vigilant of potential complications during these periods. Early identification of complications can help differentiate between tumor progression and treatment-related conditions such as sarcoid-like reactions, which could otherwise be misinterpreted as disease progression.

The onset of complications related to immunotherapy and CAR-T cell therapy varies depending on the specific treatment and the type of complications. For ICIs, the onset of irAEs typically occurs within weeks to months after the initiation of therapy but can also appear much later. GI complications, such as immune-mediated colitis, usually develop within 6–8 weeks [20]. Hepatotoxicity, such as immune-mediated hepatitis, tends to appear approximately 8–12 weeks after starting therapy [26]. Endocrinopathies, including thyroiditis and adrenal insufficiency, may present later, often 9–12 weeks, or even several months into treatment [5]. Pneumonitis typically occurs within 2–6 months but can be delayed [21].

CAR-T cell therapy is associated with more immediate complications, with CRS typically presenting within a few days to weeks after infusion, and the majority of cases occur within the first week. ICANS usually develops within several days post-infusion, often coinciding with or following the onset of CRS [31,32].

CONCLUSION

The advent of new anticancer drugs, including MTTs, ICIs, CAR-T therapies, and ADCs, has introduced a variety of drug-specific toxicities. The rapid evolution of these novel treatments poses a challenge in maintaining up-to-date knowledge of drug complications and associated imaging findings. Nonetheless, a thorough understanding of drug-specific toxicities, as reflected in medical imaging, is crucial for optimal patient care. Radiologists, in collaboration with clinicians, must adopt a multidisciplinary approach that utilizes both imaging and clinical data to provide the best care for patients with cancer treated with these innovative therapies. Consequently, radiologists must stay informed about the imaging characteristics of complications and their underlying mechanisms related to new cancer treatments.