Abstract
Since the introduction of immunotherapy and targeted therapies, patients not only have adequate tumoral response to these treatments, but their quality of life has improved due to milder toxicities. However, due to their wide mechanisms of action, the toxicity profile for these therapies is broad, can have an insidious onset, and their recognition can be challenging. Rarely, some of these toxicities can cause significant morbidity if not diagnosed early and lead to intensive care unit (ICU) admission and death. Anesthesiologists are likely to encounter not only a wide spectrum of these toxicities but also a wide range of severity. In some cases, they could be the first to make the diagnosis and therefore need to be prepared to rapidly assess, establish differentials, perform a diagnostic workup, and evaluate the impact the toxicity could have on the patients’ care during the perioperative period. In this article, we set to review toxicities of novel cancer therapies such as checkpoint inhibitors and targeted therapies, that could present in the perioperative setting. This article will help as a guide for anesthesiologists to recognize their clinical presentation, the approach to their diagnosis, and their impact on patient care.
Since the advent of immunotherapy and targeted therapies, patients can have adequate tumoral regression with milder toxicities. However, due to their wide mechanisms of action, the toxicity profile for these treatments is broad, can have an insidious onset, and their recognition can be challenging and require a high degree of clinical suspicion.1 Rarely, some of these toxicities can cause significant morbidity if not diagnosed early and lead to intensive care unit (ICU) admission. Anesthesiologists are likely to encounter not only a wide spectrum of these toxicities but also a wide range of severity. In some cases, they could be the first to make this diagnosis and therefore need to be capable of rapidly assessing, establishing differentials, and evaluating the impact the toxicity could have on the patients’ care during the perioperative period.
In this article, we set to review the toxicities of novel cancer therapies that could present in the perioperative setting. This article will focus on targeted therapies and checkpoint inhibitors as their toxicities are very likely to present at different time periods of the perioperative setting. We will present case-based examples that highlight the toxicities of these treatments in different settings, the approach to their diagnosis, and their impact on patient care. Other immunotherapies, such as adoptive cell therapies, and their perioperative approach and ICU care for treatment-related toxicities, will not be the focus of this article and a detailed approach to these scenarios is available in the literature.2,3
BACKGROUND
Over the past 2 decades, the development of targeted therapies and immunotherapies has changed the landscape of cancer care. The role the immune system plays in cancer progression was first described in the early 1900s.2 Agents such as vaccines, cytokines, and modified cells were later designed to enhance the patients’ immune system and destroy cancer cells. Many of these therapies are now approved for the treatment of multiple malignancies and include adoptive cell therapy (such as chimeric antigen receptor [CAR] T-cells), immune checkpoint inhibitors (ICIs), bispecific monoclonal antibodies (mAbs), and cancer vaccines. Targeted therapies are designed to recognize specific tumoral proteins, antigens, or pathways that inhibit tumoral growth. The first targeted therapy approved for cancer was Rituximab for the treatment of lymphoma in the 1990s.4 The response to some of these therapies has been so robust in some patients, that more than 50 drugs are approved yearly for cancer treatment.5,6 These treatments are now so common that most Anesthesiologists will be exposed to patients with their toxicities at some point in their career. Usually, their presentation can be mild and nonlimiting, but in some cases, they can require ICU admission.
The severity of toxicities from these therapies is graded using Common Terminology Criteria for Adverse Events (CTCAE) on a scale from 1 to 5 (1 = mild; 2 = moderate; 3 = severe; 4 = life-threatening; 5 = death).7 Treatment will vary depending on the pathophysiology, severity, and cause of this toxicity. An understanding of the mechanism of action of both targeted therapies and checkpoint inhibitors can help simplify the approach to their toxicities. The evaluation of cancer patients receiving these therapies in the perioperative setting should include a review of general risk factors related to the procedure, recognition of the therapies received, and significant comorbidities. A system-based approach should be implemented as it can help simplify the process of identifying possible toxicities (Table 1). Moreover, documentation in the electronic medical record of any of these toxicities will be of extreme importance for other anesthesia providers when evaluating patients for future procedures. Therefore, documentation of the agent, date of toxicity, and treatment required should be considered as part of the documentation during the preoperative assessment. Centers within the United States have created their own guidelines for the evaluation and workup in the preoperative setting of patients receiving ICIs, and can be used as a framework for anesthesia providers.8
| Adverse events | Preoperative considerations | Comments | |
|---|---|---|---|
| Neurologic | PRES Seizures Stroke (ischemic/hemorrhagic) Guillain-Barre syndrome Myasthenia Gravis Neuropathy Meningitis Encephalitis Subdural hematoma |
• Baseline cognitive function and neurologic examination
• History of seizures • Electrolytes abnormalities • Presence of neuropathies or neuromuscular disorders |
• Review recent imaging (CT, MRI, angiography) • Continue antiepileptic drug regimen (AED) in consultation with Neurology • Anesthesia may be needed for MRI as part of the diagnostic work up in patients with encephalopathy Intraoperative considerations: |
| Cardiovascular | Myocarditis Pericarditis Arrythmias Heart failure Pleural effusion Conduction abnormalities Acute coronary syndrome QT prolongation Hypersensitivity reactions |
• Assess exercise tolerance (METs) • Preexisting cardiovascular disease • Antiplatelet therapy • Presence of infection/sepsis • Hypersensitivity reactions are more common with mAbs (rituximab) • QT prolongation can be seen with TKIs |
• Review cardiovascular medications, electrolytes, ECG, echocardiogram, cardiac biomarkers • For high-risk patients, consider cardiopulmonary exercise testing (CPET) • Coordination of care for patients on antiplatelet therapy • Discuss need for perioperative corticosteroids and diuretics • Discussion with cardiologist for those patients with suspicion or history of cardiotoxicity Intraoperative considerations: |
| Pulmonary | Pneumonitis Alveolar hemorrhage Pulmonary Edema Pulmonary hypertension ARDS Sarcoidosis Thromboembolism |
• History of radiation therapy • Baseline oxygen requirements • Bronchodilator and corticosteroid regimen • Optimization of underlying pulmonary disease • Recent or current pulmonary infections • Anticoagulant therapy/IVC filter for thromboembolic disease • Pneumonitis can occur with ICIs, mAbs, or TKIs |
• Review imaging, PFTs, and pulmonary regimen. • Consider 6-minute walk test to assess lung function • Discuss with pulmonologist need for additional perioperative corticosteroids and bronchodilator therapy • Coordination of care for patients on anticoagulation • Consider not al patients with pneumonitis will be symptomatic therefore referral to a pulmonologist is important Intraoperative considerations: |
| Gastrointestinal | Colitis Hepatitis Pancreatitis Enteritis Gastritis |
• Diarrhea work up should rule out infectious causes (ie C. difficle) • Presence of metabolic or electrolyte abnormalities • Assess volume status for dehydration • Transaminitis can occur with or without hyperbilirubinemia, very common with TKIs • Colitis most commonly presents as diarrhea • Diarrhea can be caused by ICI, mAbs, TKIs |
• Antimotility agents typically used once infectious diarrhea has been ruled out • Avoid hepatoxic medications • Patients are likely to need Gastroenterology evaluation before initiating perioperative corticosteroids • Anesthesia may be needed for endoscopy as part of the diagnostic work up Intraoperative considerations: |
| Endocrine | Hypophysitis Thyroid dysfunction Adrenal Insufficiency Diabetes Mellitus Type 1 |
• Assess for electrolyte abnormalities
• Baseline hemodynamic assessment for patients with adrenal insufficiency • Hyperthyroidism and hypothyroidism can be present during treatment course • Treatment often continued if hormone supplementation is optimized • Endocrinopathies are more common with ICI therapy |
• Review labs for hormone insufficiencies • MRI helpful in diagnosing hypophysitis Intraoperative considerations: |
| Renal | Interstitial nephritis Glomerulonephritis Tumor lysis syndrome Nephrotic syndrome |
• Electrolyte abnormalities • Volume status • Dialysis Schedule • Interstitial nephritis can occur with mAbs, ICI, TKIs |
• Review labs, urine analysis, urine osmolarity, • Avoid nephrotoxic medications • Renal biopsy can assist with diagnosis but not mandatory • Renal consultation |
| Hematologic | Anemia Neutropenia Acquired hemophilia Thrombocytopenia/TTP HLH Thrombotic complications |
• Symptomatic anemia • Coagulopathies/bleeding risk • Increased risk of sepsis with neutropenia • DVT prophylaxis • HLH can occur with ICI and mAbs although very rare • Cytopenia can be common with some targeted therapies |
• Check laboratory tests • Consider thromboelastography to assess clotting function • Tranexamic acid perioperatively in high-risk cases • Discuss perioperative antibiotics • Consider hemorrhagic and thrombotic complications with antiVEGF therapy • Consider perioperative hematologic consultation Intraoperative considerations: |
Targeted Therapies
Targeted therapies are designed to recognize specific tumoral antigens, hormonal receptors, molecules, or enzymes that interfere with the proliferation of cancer cells.6 Targeted therapies can be divided into 2 types according to their mechanism of action: kinase inhibitors (KIs) and mAbs. The mechanism of action of KIs is usually intracellular and they inhibit kinases, enzymes that play a key role in cellular growth, proliferation, and apoptosis.6,9 mAbs, usually bind to extracellular molecules, proteins, ligands, and receptors that affect the survival of cancer cells.6 At the same time, KIs can also be stratified according to their mechanism of action: Receptor tyrosine KIs (which can be mAbs and KIs), nonreceptor tyrosine KIs, and downstream signaling inhibitors (KIs).6,9 Targeted therapies are approved for the treatment of both solid and hematologic malignancies, and many other are currently under investigation.9Table 2 summarizes the current US Food and Drug Administration-approved targeted therapies, mechanism of action, and toxicities relevant to the perioperative setting.
| Type/target | Generic name | Organ system affected | Toxicitya | Comments |
|---|---|---|---|---|
| Kinase inhibitors | ||||
| VEGFR | Aflibercepta SorafenibSo SunitinibS VandetanibV |
Cardiovascular
Pulmonary CNS Endocrine Other |
QTc ProlongationV,S HypertensionS, So, DysrrhythmiasA PneumonitisV,So,S PRESV,So,S HypothyroidismS,So Thrombosis S,So |
-Recommendations available for cardiovascular monitoring for patients at risk for depressed EF10
-ECG and arrhythmia monitoring in the perioperative period is recommended -Grade of pneumonitis could carry significant morbidity in the operative and postoperative setting therefore careful evaluation with a pulmonologist is recommended – Consider optimization in the preoperative period and intraoperatively for those patients with significant PAH |
| EGFR | GefitinibG OsimertinibO VandetanibV ErlotinibE |
Pulmonary
Cardiovascular Gastrointestinal Endocrine Other |
Pneumonitis/ILDO,G
Heart failureO TransaminitisG HypothyroidismV TMAE |
-Neurological toxicities are likely to be encountered in the ICU setting (refer to for approach to GBS and MG) |
| HER2 | LapatinibL TucatinibT |
Cardiovascular | Low EF cardiomyopathyL,T | |
| ALK/EGFR ALK/ROS |
BrigatinibB CrizotinibC |
Cardiovascular
Pulmonary |
QTc prolongationC
PneumonitisT,C |
|
| BCR-ABL | DasatinibD NilotinibN PonatinibP Imatinibi |
Cardiovascular
Pulmonary CNS Endocrine Other |
Acute coronary syndromeP,N QTc prolongationD,P Left ventricular dysfunctioni PAHD ICH and SDHi HypoglycemiaD,i ThromboembolismP,D |
|
| BTK | IbrutinibI AcalabrutinibA |
Cardiovascular
Other |
HypertensionI,A Atrial fibrillationI,A BleedingI,A |
|
| PARP | Olaparib | Pulmonary | ILD | |
| HDAC inhibitors | RomidepsinR VorinostatV |
Cardiovascular | QTc prolongationR,V | |
| MEK inhibitors | Trametinib | Cardiovascular | Left ventricular dysfunction | |
| Proteosome inhibitors | BortezomibB CarfilzomibC |
Pulmonary | PneumonitisB,C PAHP |
|
| Monoclonal antibodies | ||||
| VEGFR | BevacizumabB RamucirumabR |
Cardiovascular
Other |
HypertensionB Left ventricular dysfunctionB BleedingB |
-Risk of cardiomyopathy with trastuzumab can increase to 30% if in combination with anthracycline based chemotherapy. Therefore consider when assessing patients in the preoperative setting
-ECG evaluation in the preoperative period is important |
| HER2 | TrastuzumabT b PertuzumabP |
Cardiovascular
Pulmonary |
Low EF cardiomyopathyT,P
PneumonitisT |
-Grade of pneumonitis could carry significant morbidity in the operative and postoperative setting therefore careful evaluation with a pulmonologist is recommended
Intraoperative considerations: |
| CD20 | Rituximab | Cardiovascular
Pulmonary |
Dysrhythmias Infusion reactions Pneumonitis |
-Bleeding complications with bevacizumab are not significant intraoperatively -Approach to those patients with findings of pneumonitis on imaging should be similar to ICI intraoperatively. -Monitor closely for dysrhythmias |
| EGFR | CetuximabC PanitumumabP |
Pulmonary | PneumonitisC,P | |
In comparison to chemotherapy, which is nonselective and carries significant toxicity, toxicities from targeted therapies are considered less severe but can have a broad presentation. In some cases, such as those of angio-genesis inhibitors, toxicities are secondary to the receptor they bind to and are called “on-target toxicities” (eg, vascular complications associated with the blockade of vascular endothelial growth factor (VEGF)).1,11 Another mechanism of action for these toxicities is direct cell injury or “off-target toxicity.” This occurs when the target is found in noncancer cells and leads to direct damage of benign tissues.1,12 In some cases, multiple pathways are activated, and these mechanisms of toxicity can overlap. Some of the most significant toxicities by targeted therapies that can present in the perioperative setting include hypertension, thrombotic and bleeding complications, cardiomyopathies, dysrhythmias, pneumonitis, poor wound healing, endocrinopathies, and skin toxicities.1,4,6,9,11 The incidence and onset of these toxicities vary, but it can be insidious and sometimes associated with cumulative doses.1
Immune Checkpoint Inhibitors
ICIs are mAbs that bind to the T-cell inhibitor pathways programmed cell death protein-1 (PD-1), programmed death ligand (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) pathways. By blocking these inhibitory pathways, they enhance T-cell activation, recognition of tumoral antigens, and T-cell mediated tumoral regression.13,14 PD-1, PD-L1, and CTLA-4 ICIs work via different pathways, can be complementary, and thus are often administered concomitantly when treating some malignancies.15 ICIs have been approved for the treatment of mainly solid tumors, but also B-cell lymphomas.16 When enhancing a T-cell mediated immune response, ICIs can cause overwhelming inflammation and damage to healthy tissues resulting in autoimmune syndromes known as immune-related adverse events (irAEs). The wide spectrum of toxicity profiles of both classes of ICIs (PD-1/PD-L1 and CTLA-4) can be attributed to the difference in their mechanism of action. Although PD-1/PD-L1 targeting ICIs may be less toxic than CTLA-4 ICI, the approach to managing the irAEs caused by these agents is similar.16
The most commonly affected organ systems by irAEs are endocrine, gastrointestinal, and musculoskeletal; however, the nervous, cardiovascular, pulmonary, and renal systems pose more risk for life-threatening syndromes. Clinical manifestations of irAEs vary substantially with respect to the prediction of patients at risk, onset of timing, duration of toxicity, or likelihood of reemergence, therefore posing a challenge for their diagnosis. What is widely accepted in the literature is that irAEs may be recurrent, late-onset, or present as chronic irAEs. The rates of reemergence range from 10% to 40%, can occur in the same organ, and recur with or without restarting an ICI.17,18 Chronic irAEs, present in 25% to 35% of patients, are considered continuous ongoing toxicities persisting after ICI discontinuation and ranging from 12 weeks to 6 months.19–22 Late-onset irAEs are defined as manifesting more than 3 months after discontinuation of the ICI.20 As Anesthesiologists encounter patients at varying timelines during their neoadjuvant treatment with ICI therapy, one should be mindful that symptoms can present acutely, delayed or chronically after ICI administration.
The general management of toxicities due to ICIs and targeted therapies will not necessarily be in the purview of the anesthesiologist, unless in the ICU setting. Usually, treatment requires interruption of the agent, glucocorticoids, and alternative immunosuppressive agents such as infliximab and mycophenolate for refractory cases.23–25 Details of these afflicted organ systems and resulting symptom presentation and management are presented in Tables 2 and 3.23–25 Anesthesiologists should familiarize themselves with these syndromes, as early recognition, and referral to the appropriate consultant could avoid further progression and increased morbidity and mortality. The approach of these patients intraoperatively could vary according to the organ affected and level of injury and such considerations are presented in Table 1.
REVIEW OF CASES: PRESENTATION, DIAGNOSIS, AND MANAGEMENT
The following cases will review some of the most common and significant toxicities that anesthesia providers can be faced with. A review of their presentation, causes, workup and treatment will be discussed. While patients with a history of toxicities or with mild (grade 1–2) presentations are most likely to be encountered by anesthesiologists in the perioperative setting, Grade 3 to 4 toxicities are likely to be encountered by those who cover the acute care setting, and specifically the ICU. It is important to note that while Anesthesiologists might not necessarily initiate many of these treatments, they will play a key role in their recognition and communication with the appropriate practitioners (oncologist and necessary subspecialties) to initiate workup and a plan of care.
Case 1. Neurologic Toxicities
Case: A 65-year-old man with a medical history of hypertension, and primary renal cell carcinoma (RCC) treated with a nivolumab (PD-1) presents for a nephrectomy. The surgery was uneventful, and he was extubated in the operating room. You take over his care in the postanesthesia care unit where the patient develops dysphonia and poor respiratory effort, and an arterial blood gas reveals elevated pCO2. He is subsequently intubated and transferred to the ICU. During his ICU day 1, his chest x-ray (CXR) appears normal, and ABG normalizes with positive pressure. However, during pressure support trials, you notice that he triggers the low-minute ventilation alarm. You perform mechanics and notice a low negative inspiratory force and vital capacity. On further review with the patient’s family, they report complaints of weakness and dyspnea for weeks. On physical examination proximal weakness is noted.
Discussion
ICI-mediated neurologic toxicities are a variety of syndromes resulting from severe inflammation within the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs include myasthenia gravis (MG), Guillain-Barré syndrome (GBS), aseptic meningitis, encephalitis, transverse myelitis, central and/or peripheral neuropathy and posterior reversible encephalopathy syndrome (PRES).26–30 MG/MG-like syndrome, encephalitis, and acute immune demyelinating polyneuropathy can develop rapidly, resulting in respiratory failure requiring intubation, and be fatal.26,27,30,31 GBS and MG are probably the 2 syndromes that are most likely to have a significant impact in the perioperative setting if unrecognized. Despite the low incidence of all-grade neurological irAEs (3.8%–12%), anesthesiologists should have a high index of suspicion in the perioperative period as they have high morbidity if unrecognized and left untreated.26,27,30,31 The median time of onset of symptoms is 6 weeks, and the time to resolution has been reported around 2 to 8 weeks.26,27,32 Prompt recognition and referral to the neurologists to initiate a proper workup and treatment is critical for reducing long-term morbidity and mortality.
PNS syndromes such as GBS and MG triggered by ICI administration differ from their classic counterparts. Older patients treated with PD-1/PDL-1 are more prone to developing ICI-related MG.32,33 Bulbar symptoms (slurred speech, dysphagia, and dysphonia) and respiratory involvement are more frequent than ocular symptoms present in classic MG.34–36 Patients with concomitant immune-related peripheral neuropathy and GBS are more common in patients with melanoma and typically present with ataxia, ophthalmoplegia, areflexia, weakness, and paresthesia.28,37 Occasionally MG can present as a triad concurrently with myocarditis and myositis, or with just one of the 2 in about 16% and 51% of patients; this concurrent presentation significantly increases the patient’s mortality (from 20%–33% to 62.5%).35,38–40 Any patient with ICI-related MG/GB should undergo workup with creatinine phosphokinase (CPK), aldolase, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), electromyography (EMG), Troponin T, electrocardiography (ECG), and a transthoracic echocardiogram (TTE).23–25 Laboratory testing for antibodies against acetylcholine receptor (AchR) is recommended and is positive in approximately 58% of patients with ICI-induced MG.35,41 Conversely, the role of MusK antibodies has not been reported.35,41 Other diagnostic workup consists of pulmonary function tests (with negative inspiratory force and vital capacity), nerve conduction studies (to exclude concomitant neuropathy), lumbar puncture with cytology and magnetic resonance imaging (MRI) (to rule out metastatic or leptomeningeal disease).35 Questioning for any neurological symptoms and a complete neurological examination should be performed in the preoperative setting. Several factors, including surgery, anesthetic, and nondepolarizing neuromuscular blockade can exacerbate myasthenia or precipitate a crisis leading to respiratory failure.42 Therefore, careful planning of induction and maintenance of general anesthesia is required. Care should also be taken to avoid medications during surgery that may worsen MG (eg, beta-blockers, Ca2+ channel blockers, magnesium). Regional anesthesia is generally considered safe, however in the setting of neuropathy or GBS, it may be considered a relative contraindication. The concern remains exacerbating postoperative neurologic deficits, resulting in double-crush phenomenon or postsurgical inflammatory neuropathy.43 If regional anesthesia is considered prudent in patients with neuropathy, a comprehensive discussion detailing the risks, benefits, and alternatives should be undertaken and carefully documented.
Considerations for the ICU Provider
Management of respiratory failure due to MG and GBS, from both ICIs and targeted therapies, are the most common neurological toxicities observed in the ICU setting. Besides corticosteroids, treatment for both MG and GBS consists of plasmapheresis or intravenous immunoglobulin (IVIG) if symptoms are refractory to corticosteroids.23,25 Additional immunosuppressive therapy such as rituximab, abatacept, mycophenolate, and tacrolimus can be considered.23–25 Regular and frequent pulmonary function assessment and daily neurologic evaluation round out the management strategy.
Other neurologic complications encountered in the ICU with both therapies include aseptic meningitis, encephalitis, transverse myelitis, PRES, and both ischemic and hemorrhagic strokes. Management of these toxicities requires discontinuing the cancer therapy, corticosteroids, and other immunosuppressants when refractory.23–25
Case 2. Pulmonary Toxicities
Case: A 70-year-old man with a history of locally advanced nonsmall cell lung cancer (NSCLC) on pembrolizumab (PD-1 inhibitor), smoking, and chronic obstructive pulmonary disease. His usual treatment is not at your hospital, and he presents to the emergency room with abdominal pain and fever. On workup he is found to have free air on CXR, and CT abdominal/pelvis confirmed bowel perforation. Emergent surgery is being planned. As the Anesthesiologist, you are reviewing his CXR, which also reveals pulmonary infiltrates. On further questioning, he states he has occasional cough but not symptomatic overall and is saturating 95% on room air. His recent medication review is significant for inhaled bronchodilators and pembrolizumab. What are the necessary considerations?
Discussion
Pulmonary toxicity resulting from ICIs can manifest as pleural effusions, pulmonary sarcoidosis, sarcoid-like granulomatous reactions, and pneumonitis.44,45 The most common pulmonary toxicity is pneumonitis, with a reported all-grade incidence of 2% to 5% and 1% for severe grades.45–47 According to earlier trials, pneumonitis is more frequent in patients with NSCLC and RCC (4.1%) compared to <1% for other malignancies such as melanoma.48 Risk factors for ICI-related pneumonitis are underlying lung disease (asthma, interstitial lung disease, and chronic obstructive pulmonary disease), history of radiation, squamous tumor histology, smoking history, and combination therapy.49,50 Most pneumonitis tends to occur within 6 months of ICI initiation and real-world data suggest a temporal relation between initiation of ICI and grade of pneumonitis; early onset pneumonitis is characterized by higher severity and early mortality, while a late-onset is predominantly of lower grade with better outcomes.49
Pneumonitis should be high on the differential diagnosis in a patient who has received ICIs and presents with fever, cough, and dyspnea.45,51 However, in a third of cases, patients can be asymptomatic with significant findings on imaging, an important presentation for the Anesthesiologist. If pneumonitis is missed and left untreated, it can progress and lead to respiratory failure.45 A detailed history and physical, pulse oximetry at rest and with ambulation, and assessment of other risk factors to rule out differentials will be important. Imaging with CXR and CT chest will reveal infiltrates that can improve after withholding the offending agent. Unfortunately, CT findings are nonspecific and can vary from ground glass opacities, interstitial markings, interlobular septal thickening, dense consolidations, and nodular lesions.45,51 Often a bronchoscopy may be warranted to exclude infection and may reveal diffuse lymphocytic infiltration.49
In the case we describe, in view of mild symptoms, if the patient was evaluated for an elective surgery, consult with a pulmonologist to assess for bronchoscopy with bronchoalveolar lavage (BAL) to rule out tumor infiltration in addition to infection, is recommended. The degree of pulmonary infiltrates and hypoxemia would determine risk assessment before the surgery and morbidity during and after the procedure. In collaboration with the pulmonologist, optimization from a pulmonary standpoint before any elective procedure would be preferable. When considering an emergent case that requires immediate preoperative assessment, consultation with a pulmonologist and oncologist is strongly recommended. Additionally, as the procedure is often time-sensitive it would be prudent to initiate antimicrobial coverage, as there often isn’t enough time to perform a bronchoscopy with BAL, and corticosteroids.
Pulmonary toxicities are also described in a wide range of targeted therapies; however, their incidence is not high (<5%; Table 2).12,52–54The approach and treatment in the perioperative period for these toxicities should be similar to ICI-related pneumonitis as described above.53,54 Pleural effusions due to dasatinib are common (50% of patients) and usually respond to interruption of therapy and corticosteroids.1
Considerations for the ICU Provider
Respiratory failure due to treatment-related pneumonitis is an important presentation in the ICU. Treatment guidelines for these presentations for tyrosine kinase inhibitors (TKIs) and ICIs recommend corticosteroids and holding the agent.1,23–25 On the contrary, in patients receiving mTOR inhibitors for RCC, the presence of pneumonitis has been associated with tumoral response and therefore treatment could continue while monitoring symptoms.55 Approximately 40% of patients with severe toxicities will require additional immunosuppression with infliximab or with cyclophosphamide.45 Careful discussion with the oncologist and pulmonary team will be of extreme importance to rule out other possible causes of respiratory failure, timing of other immunosuppressants and discussion of prognosis.
Case 3: Complications Associated with Angiogenesis Inhibitors
Case: A 40-year-old man with a history of colon cancer is admitted for a planned lung biopsy under anesthesia. On preoperative evaluation, he has no other significant comorbidities, has a good functional status, and his only active medication is bevacizumab for treatment of his cancer, which he received 20 days ago. As the case is finishing, the patient acutely becomes hypoxic, hypotensive, and tachycardic. He is intubated and a TEE is performed which shows elevated pulmonary pressures and signs of right ventricular (RV) overload. The patient’s hemodynamics and oxygenation stabilize, and a CT angiography is performed which showed a right main pulmonary artery embolism with RV strain. The patient undergoes catheter-directed embolectomy and later receives anticoagulation.
Discussion
Angiogenesis inhibitor targeted therapy binds the VEGF receptor to inhibit vascular proliferation and tumoral growth.56 Angiogenesis inhibitors can be mAbs (eg, bevacizumab) or TKIs (eg, sunitinib and sorafenib).56 These treatments are now approved for the treatment of malignancies such as RCC, glioblastoma, colorectal cancer, neuroendocrine tumors, NSCLC and hepatocellular carcinoma.6 Due to their mechanism of action, their main toxicities are related to vascular complications such as thrombotic events (arterial and venous), bleeding and uncontrolled hypertension.1,11,57 Cardiotoxicity, such as depressed ejection fraction(EF), QTc prolongation, and dysrhythmias can occur.1,58,59
Venous thrombosis with antiVEGF therapy, such as in our case, is more prevalent with bevacizumab (5% prevalence), and can be severe in 1.8% of patients.11 Venous thrombotic events include thrombophlebitis, pulmonary embolism, mesenteric venous occlusion, and retinal vein thrombosis.60 The incidence of arterial thrombosis tends to be lower (<3%) and cases reported include ischemic strokes, myocardial infraction, and extremity arterial thrombosis.11,60,61 Even though these rates seem low, it is 3 times higher than cancer patients receiving other types of therapies, therefore close clinical monitoring for these complications is extremely important.1,60 Risk factors for arterial thrombosis include patients with prior history of thromboembolic events and those older than 65.60,61 The assessment and management of these thrombotic complications should not differ from published guidelines.
AntiVEGF therapy is also associated with bleeding and is more common with TKIs (soratenib and sunitinib).62,63 It can present as a tumoral bleed, pulmonary hemorrhage, epistaxis, and hemorrhagic strokes all of which are more likely to be observed in the ICU setting.11,62 The incidence of severe hemorrhagic complications is reported to be 2% to 5%, which can be worrisome in a patient population that is already known to have an increased risk of bleeding diathesis.1,11,62 Currently, there is no evidence to suggest that bleeding is worse during the operative course in patients taking these therapies.64 Assessment and management of hemorrhagic complications should not differ from that of any other cause of hemorrhage.
Important considerations during the history and examination of patients receiving antiVEGF therapy include assessing cardiovascular risk factors, symptoms, signs of uncontrolled hypertension, and assessment of risk factors for venous thrombosis and arterial thrombosis. ECG, electrolytes, and a TTE (specially in those with cardiac symptoms or significant cardiovascular risk factors) should be part of the preoperative evaluation. Monitoring for dysrhythmias should occur in the pre and postoperative setting. Hypertension is common with sunitinib, however malignant hypertension is rare. In these cases, the TKI should be held until the blood pressure is controlled with antihypertensives and can be resumed with close monitoring.1,57 Lastly, due to decreased wound healing, it is recommended to hold bevacizumab for at least 28 days before any planned procedure.4,64 For those patients in whom the procedure was emergent, careful examination of the wound in the postoperative setting is important.
Case 4. Cardiotoxicity: Myocarditis From Checkpoint Inhibitors and Other Toxicities
Case: A 65-year-old woman with right lower lobe adenocarcinoma treated with chemoimmunotherapy regimen of carboplatin, pemetrexed, and pembrolizumab presents for right lower lobectomy via thoracotomy 7 weeks after starting treatment. Her medical history is significant for hypertension. She had normal pretreatment cardiac biomarkers, TTE, and ECG. Intraoperatively, after surgical incision, she had refractory tachycardia and multiple runs of nonsustained ventricular tachycardia. The procedure was aborted due to unstable hemodynamics. Her cardiac evaluation revealed elevated cardiac biomarkers, ECG changes consistent with myocardial ischemia, and a TTE with evidence of global left ventricular dysfunction. Left heart catheterization was negative for obstructive coronary artery disease and acute coronary vasospasm, prompting cardiac biopsy, which confirmed the diagnosis of Immune Checkpoint Inhibitor Associated Myocarditis (ICI myocarditis). Immunomodulators were initiated as part of her treatment.
Discussion
Cardiovascular irAEs occur in <2% of patients treated with ICIs. Myocarditis is the most common cardiovascular irAE and carries the highest mortality rate (25–50%).65–68 The exact mechanism of ICI-related myocarditis is unknown; however, a T-cell mediated inflammatory response plays a role as T-cell infiltration into the myocardium is observed on biopsy.67 Myocarditis typically presents within 1 to 3 months of treatment but can occur as early as 2 weeks or as late as a year after the last dose of ICIs.67,69 Patients receiving combination therapy with anti-PD-1 and antiCTLA-4 are more likely to develop ICI myocarditis than with either one alone.38,66–68 Furthermore, it is noteworthy that 40% of patients with myocarditis will also have myositis, a comorbidity associated with a 13-fold increase in mortality.39,40 In these cases, CK levels are helpful for diagnosis and tracking response to corticosteroid therapy.40 Patients with ICI-related myocarditis can be asymptomatic, and have nonspecific symptoms such as fatigue, chest pain, hypotension, arrythmias, heart failure or develop sudden cardiac death. Even in patients who are asymptomatic, elevated cardiac biomarkers alone can be associated with sudden death.10 Hence, awareness and a strong clinical suspicion are key to obtaining the appropriate cardiac workup.
Guidelines are available for workup, grading, and management of cardiovascular irAEs.23–25,54 ICI myocarditis represents a diagnostic challenge given the low overall incidence.66 Due to its high morbidity and mortality, all patients receiving ICIs should be routinely monitored with cardiac biomarkers and an ECG.8,23,70 In the preoperative setting, even if a patient is asymptomatic, it is imperative to review if these tests have been performed within 1 month of a treatment since they can be abnormal in as many as 85% to 94% of patients with myocarditis.8,68,70,71 ECG findings such as prolonged PR interval, premature ventricular contractions, atrioventricular block, ST changes, or ventricular arrhythmias, are present in as many as 85% of patients.67,70 Consequently, the diagnosis of ICI myocarditis necessitates a comprehensive approach that includes modalities such as CXR, TTE, and cardiac magnetic resonance imaging (CMR) to aid with differentials and assess the presence of cardiopulmonary disease, diastolic dysfunction, wall motion abnormalities, and pericardial effusion.10,67 Lastly, a negative CMR or TTE does not rule out myocarditis and the gold standard is a myocardial biopsy.10 If any of these tests are suggestive of cardiac toxicities during the perioperative period, a consultation with a cardiologist will facilitate the diagnostic process and determine the need for cardiac catheterization, myocardial biopsy and guide treatment.23,67,68,70,72,73 Consequently, it is important to rule out other causes of cardiac disease and the presence of concurrent disease processes as patients can have concomitant cardiac risk factors.68 It is important to note that the Anesthesiologist might encounter cases of asymptomatic cardiotoxicity where ICI therapy was resumed while monitoring for any worsening toxicities.23–25 In such cases, a preoperative assessment by the cardiologist is recommended to assess the cardiac risk, optimization, and further workup that could be necessary before any procedure.
Targeted therapies are also associated with cardiac complications that could be significant for the anesthesia care provider.74 Traztuzumab, an anti-Human epidermal growth factor receptor 2 mAb, is associated with low EF cardiomyopathy in as many as 25% of patients.1,75 QTc prolongation, pulmonary hypertension (PAH) and arrhythmias have been described with TKIs58,76,77 (Table 2). A careful clinical history and preoperative cardiac evaluation of these patients is recommended. Different from checkpoint inhibitors, use of biomarkers alone might not always yield a diagnosis of cardiac involvement with these agents.78 Currently, the use of TTE is recommended routinely in those patients who have received trastuzumab and other antiVEGFs.78 If a patient has risks for underlying coronary artery disease, a preoperative ECG and TTE should be considered especially in those patients who have received a breakpoint cluster region-abelson TKI (ponatinib, nilotinib).2,76,78 Patients receiving dasatinib and imatinib can develop PAH, which resolves with their discontinuation.1,76,77 While rare, recommendations are to screen with a TTE while receiving this therapy. If a patient is undergoing a high-risk procedure, and there is no recent TTE, Anesthesiologists should consider performing one perioperatively to screen for PAH and assess RV function.
Considerations for the ICU Provider
In the ICU, grade 2 to 4 irAEs (mild symptoms, depressed EF, positive CMR or cardiovascular compromise) will likely be encountered, and close monitoring and close collaboration during treatment with the cardiologist is warranted.23–25 The mainstay of treatment is supportive management for arrhythmias and hemodynamic compromise. Initiating corticosteroid therapy is considered an emergency, and patients should receive 1gm of solumedrol without delay, while diagnostic workup is initiated.10 Escalation of treatment with other immunosuppressants such as mycophenolate, infliximab, antithymocyte globulin, or abatacept should be considered early on.23–25
Case 5. Endocrinopathies
Case:73-year-old man with stage IV melanoma presents for a liver biopsy under anesthesia after his third cycle of treatment with nivolumab and ipilimumab (CTLA-4 inhibitor). His past medical history is significant for hypertension and type 2 diabetes mellitus. He reports worsening fatigue, an occasional headache, and poor appetite since his last treatment 3 weeks ago. Preoperative laboratory values are significant for a serum sodium 130 mmol/L, potassium 5.5 mmol/L, and glucose 50 mg/dL. His blood pressure is 92/43 and he is in sinus tachycardia with a heart rate of 114. The case is canceled for clinical optimization and an endocrine workup is initiated. Serum markers show low levels of thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and follicle-stimulating hormone (FSH). A brain MRI shows an enlarged pituitary gland further confirming the diagnosis of ICI hypophysitis.
Discussion
Endocrinopathies due to ICIs have been described extensively in the literature. Hypophysitis is more common in patients receiving combination therapy (10%) followed by monotherapy with anti-CTLA4 (5%).79 The pathophysiology of ICI hypophysitis has not been completely elucidated but represents a form of secondary hypophysitis due to inflammation of the anterior pituitary gland. Patients may experience this condition between 9 and 28 weeks after the initiation of therapy.73,80 The clinical presentation can be nonspecific, with symptoms ranging from headaches and visual disturbances, to generalized fatigue, anorexia, or loss of libido.80 Additionally, the hormone imbalances may not always correlate well with the clinical picture, and the patient’s treatment history might be the only clue to this disorder.
Endocrinopathies related to ICIs present a diagnostic challenge due to nonspecific symptomatology and the need to differentiate primary versus secondary disorders. Moreover, complex cases such as pituitary apoplexy or euthyroid sick syndrome may mimic ICI hypophysitis clinically, but the etiology typically stems from pituitary hypoperfusion, trauma, surgery, infection, or septic shock.81 Additionally, the clinical picture for adrenal insufficiency can be confounded by its similarity to septic shock or syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hence, the vast paradigm of clinical features resulting from ICI hypophysitis highlights the importance of careful evaluation with consultation from an endocrinologist to ensure the appropriate diagnosis and treatment. Other endocrinopathies associated with ICIs include new-onset diabetes mellitus, which can present as hyperglycemic emergencies due to pancreatic failure (in the setting of T-cell infiltration of the pancreas).16 Therefore, a high suspicion for these pathologies is needed when assessing preoperative laboratory abnormalities in patients with a history of ICI treatment.
Because up to 40% of patients treated with ICI experience endocrinopathies, patients undergo routine laboratory testing during treatment to detect hormone imbalances.82,83 Workup should include TSH, free triiodothyronine (FT3), and free thyroxine (FT4) to assess the thyroid axis; ACTH and cortisol to assess the adrenal axis; and FSH, luteinizing hormone (LH), Testosterone/Estradiol assess the gonadal axis.8,16,79 Assessment of these levels in the preoperative evaluation is extremely important (especially when considering adrenal insufficiency). Thyroid dysfunction is the most common, occurring in up to 15% of patients.84 Patients can experience hyperthyroidism, hypothyroidism, or both disorders during their treatment course. Hormone levels should be accompanied by an MRI brain to confirm the presence of an enlarged pituitary gland, which is pathognomonic; however, diagnosis can be based on clinical or laboratory findings.73,80 Most patients on ICI therapy experience mild to moderate (Grades 1–2) symptoms of hypophysitis and other endocrinopathies. Consequently, with appropriate hormonal replacement (including corticosteroids for patients with adrenal insufficiency), ICI therapy can be continued unless symptoms were life-threatening.79
Endocrinopathies such as hypothyroidism and hyper/hypoglycemia, are described with targeted therapies. Hypothyroidism is one of the most common complications, presenting in 80% of patients treated with sunitinib.1,57 Its treatment is thyroid hormone replacement while continuing the TKI. Adjustment of diabetes medications might be required as hypoglycemia and hyperglycemia have been described with different TKIs.1,6,85 Close monitoring of blood sugar during the pre- and postoperative setting might be necessary for those with risk factors of hyper or hypoglycemia. Hyperparathyroidism has been described however electrolyte imbalances have not been reported to be significant and no monitoring is recommended.1
Other Considerations
Other reported toxicities of KIs and ICIs include cytopenias, renal failure, liver function test abnormalities, and diarrhea/colitis.1,6,16 These might not always be severe enough to have an impact during the perioperative setting; however, Tables 1–3 address these toxicities and considerations that could be relevant to the Anesthesiologist. TTP and acquired hemophilia have been described with ICIs, therefore a collaborative approach with hematologists on how to approach bleeding diathesis in patients requiring emergent surgical interventions is highly recommended.86 Regarding patients with cutaneous toxicities, which are observed with both ICIs and TKIs, diligent attention should be directed towards monitoring the impact of adhesives, positioning, and instrumentation on skin integrity.1,16 Such toxicities and care implemented during the OR should be carefully documented in the medical record so these approaches can be reproduced during future procedures. Lastly, as pain management is a significant part of anesthesia care, it is important to note that data suggest that use of opioids could impact CD8 T-cell activity and therefore ICI-related tumoral response.87,88 This further emphasizes the importance of interventions such as enhanced recovery after surgery (ERAS) and evaluation of nonopioid interventions for chronic cancer pain.
| Organ system | Immune-related adverse events | Diagnostic workup | Considerationsa |
|---|---|---|---|
| Gastrointestinal | Hepatitis and colitis | Laboratory tests (CMP), every 1–2 d; LFTs. Rule out other etiologies, Biopsy is required to confirm the diagnosis |
• Hepatology and GI consult for confirmatory diagnosis and treatment with steroids • Optimize electrolytes and fluid status before OR in patients with significant diarrhea |
| Hematologic | Autoimmune hemolytic anemia (AIHA) | CBC with anemia, macrocytosis, hemolysis on peripheral smear. Other workup for hematologic disordersb | • Hematology consult • RBC transfusion as per standard guidelines |
| Acquired TTP: Grades 3–4: thrombocytopenia, anemia, renal insufficiency, Life-threatening consequences (eg, CNS hemorrhage or thrombosis/embolism, renal failure) |
In addition to hematological panelb recommend ADAMTS13; CMV serology, CT/MRI brain; TTE, ECG; viral studies |
• Hematology consult in case of emergent operative cases to help with approach of bleeding diathesis in these cases (same as for hemophilia)
• Initiate PLEX and corticosteroids |
|
| Hemolytic uremic syndrome (HUS):
Grade 3: Clinical consequences (Renal insufficiency, petechiae) Grade 4: Life-threatening consequences (CNS thrombosis/embolism/renal failure) |
In addition to hematologic panelb, recommend viral studies, nutritional assessment Bone marrow aspirate/analysis, and workup for HUS |
• Likely to be observed in the ICU setting
• Eculizumab is recommended |
|
| Acquired hemophilia | In addition to hematologic labsb | • Hematology consult
• Factor replacement as per ASH guidelines |
|
| Dermatologic | Bullous dermatoses (bullous pemphigoid, autoimmune bullous dermatoses, bullous drug reaction), Stevens-Johnson Syndrome (SJS); Toxic epidermal necrosis (TEN); and Drug reaction with eosinophilia and systemic symptoms [DRESS] Grades 3–4: skin sloughing or blisters >30% BSA, associated fluid or electrolyte abnormalities |
Consider serum antibody tests to rule out bullous pemphigoid Rule out infectious etiology or other systemic illness Skin biopsy |
• Dermatology consult • Grades 3–4 will require ICU admission and likely referral to a specialized burn center • Care of patients in the OR monitoring impact of position and adhesives |
| Renal | Tubulointerstitial nephritis (TIN) (more common) and nephrotic syndromes | Urinalysis (sterile pyuria), Creatinine and protein ratio (low-grade proteinuria), autoimmune workup, consider renal biopsy | • Nephrology consult before considering procedures and immunosuppressive treatment |
| Cardiovascular | Myocarditis, Pericarditis, Arrhythmias, Impaired ventricular function, conduction abnormalities
Form asymptomatic with positive serum cardiac markers or mild symptoms (grades 1–2) to |
Cardiac biomarkers, EKG, Inflammatory biomarkers (ESR, CRP, WBC) Transthoracic echocardiogram, Cardiac MRI, Endomyocardial biopsy (gold standard) |
• Transient pacemaker and hemodynamic support for arrhythmias and shock
• Cardiology consult (for suspicion of toxicity or any patient with a history of cardiotoxicity who has resumed therapy) for optimization and assessment of cardiovascular risk • Preoperative cardiac evaluation in both asymptomatic and symptomatic patients |
| Neurological | Myasthenia gravis (MG) and GBS | MRI brain and spine, NIF, Vital Capacity, serum AchR & antiMuSK antibody level, ESR, CRP, EMG, NCS, LP, EMG, Nerve conduction studies, ganglioside antibody panel of blood and CSF. |
• Cautious use of NMBs or medications that could lead to exacerbation in the OR setting • ≥Grade 3 should be admitted to ICU for monitoring • Expert neurology consultation • Frequent pulmonary assessment |
| Encephalitis/aseptic meningitis/seizures, PRES
Presentation for aseptic meningitis is different from encephalitis |
Workup to rule out other causes for altered sensorium (CT and MRI brain, EEG, lumbar puncture) Autoimmune encephalopathy and paraneoplastic panels in blood and CSF Thyroid panel Exclude infection |
• Usually encountered in the ICU setting • Antiseizure medications and BP control in the case of PRES • Empiric coverage for viral etiology until ruled out |
|
| Pulmonary | Pneumonitis Grade 2: Presence of new/worsening symptoms including shortness of breath, cough, chest pain, fever, and increased oxygen requirement Grades 3–4: involve >50% of parenchyma or all lung lobes. |
CT Chest Infectious workup (viral swab, blood culture, urine culture and sputum culture), Bronchoscopy with BAL |
• Patients with a history of prior pneumonitis (who resumed ICI or on treatment or residual lung injury) and those with asymptomatic pneumonitis (findings on imaging during the preoperative setting) should be evaluated in conjunction with pulmonologist to assess optimization and morbidity |
| Endocrinology | Hypophysitis Grades 3–4: adrenal crisis, severe headache, visual field deficiency hypothyroidism, hyperthyroidism and diabetes |
ACTH, TSH, Testosterone, estradiol levels; LH and FSH; Work up for hypernatremia (concern for diabetes insipidus); MRI brain |
• Patients will require hormonal therapy in conjunction of endocrine evaluation. • Serial monitoring of these tests is recommended even in patients who are asymptomatic (therefore should be routine in the preoperative evaluation) • Consider stress dose steroids when undergoing procedures • Treatment for adrenal crisis as per standard guidelines |
CONCLUSIONS
Targeted therapies and checkpoint inhibitors have revolutionized cancer treatment and have brought a new spectrum of toxicities that anesthesiologists are likely to encounter during the perioperative setting. An understanding of the mechanism of action of these therapies can help simplify the approach to their toxicities. In the perioperative setting, the evaluation of patients who receive these treatments should include a review of general risk factors related to the procedure, recognition of the therapies received, significant comorbidities and a system-based approach to identify possible toxicities. Early recognition, workup, and treatment can reduce morbidity in the intraoperative and postoperative setting and reduce mortality.