Hi, this is Steve Pastores. I'm going to talk about oncologic emergencies for this multiprofessional critical care review course for adults. The objectives of my talk are to review and recognize the management of classic and novel oncologic emergencies, discuss the risk factors and treatment approaches for metabolic syndromes such as tumor lysis syndrome and hypercalcemia, and describe the clinical presentation and management of emergencies related to hematologic malignancies and immunotherapies for cancer. In 2021, an estimated 1.9 million new cancer cases were estimated, resulting in approximately 610,000 deaths from cancer. Cancer patients account between 6% and 20% of ICU patients. These are some of the oncologic emergencies that I'm going to focus on in my talk today. We can divide them into five buckets, metabolic, structural, cardiopulmonary, malignancy-related, and most recently immunotherapy-related, such as with CAR T-cell therapy as well as toxicities from immune checkpoint inhibitors. Let's talk about tumor lysis syndrome. This is the most common malignancy-related emergency. It's caused by rapid lysis of tumor cells. This can occur spontaneously, such as with high-grade malignancies, such as Burkitt's lymphoma, acute myelogenous leukemia, anaplastic large T-cell or diffuse large B-cell lymphoma, or more commonly, tumor lysis syndrome occurs after receiving cytotoxic chemotherapy. But besides hematologic malignancies, tumor lysis syndrome can also be seen in patients with solid tumors, such as gastric, lung, and breast cancer, and in patients with large tumor burden who are receiving brutant tyrosine inhibitors, such as ibrutinib, and PD-1 inhibitors, such as nivolumab, pembrolizumab, radiation therapy, and high-dose steroids. Tumor lysis syndrome is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypokalcemia. There are many risk factors for tumor lysis to develop. They include preexisting hyperuricemia. Patients with rapidly growing tumors are more susceptible. Those with high-grade malignancies, as I previously mentioned, those with preexisting renal dysfunction, and volume-depleted patients. The grading of tumor lysis syndrome is usually by either laboratory or clinical tumor lysis syndrome. Laboratory TLS is associated with the presence of 25% increase in uric acid levels, increase in potassium over 6, or phosphorus 6.5 milligrams per deciliter or more, and or a 25% decrease in calcium within three days before and seven days after the initiation of cytotoxic treatment. Clinical TLS, on the other hand, is the presence of laboratory TLS findings accompanied by acute renal failure with rise in creatinine to one and a half times or more the upper limit of normal, the presence of seizures, cardiac arrhythmias, or sudden death. Patients with grade 3 and 4 TLS require immediate and aggressive management in the intensive care unit setting. The treatment of tumor lysis syndrome involves the administration of intravenous fluids to maintain a high urine output and correction of electrolyte abnormalities. Diuretics can be considered to increase urine output but have not been shown to improve mortality. Urine alkalinization is also not recommended as it may increase phosphate and xanthine precipitation in the renal tubules. Commonly used drugs are allopurinol, which is a xanthine oxidase inhibitor. It blocks uric acid production. It's usually given 48 hours before the start of cytotoxic chemotherapy, and both oral and intravenous preparations are effective. However, allopurinol is not recommended as first-line prophylaxis for patients who are at high risk for TLS. And the reason for that is that if you have existing uric acid that's present, that still needs to be excreted, and it may take more than two days to decrease. When you give allopurinol, which allows for uric nephropathy, therefore, to occur. Rasburicase, which is a recombinant urate oxidase, is superior to allopurinol in clearing uric acid and preventing acute kidney injury. Rasburicase degrades the existing uric acid to allantoin, which tends to be more soluble than uric acid, which then can be excreted in the urine. You can see the recommended dose on the slide. Serious adverse reactions include anaphylaxis, hemolysis, and in particular, methemoglobinemia. Contraindications to rasburicase include G6PD deficiency. In patients with G6PD deficiency who receive rasburicase, you will develop hemolytic anemia. Hemodialysis, or continuous veno-veno hemofiltration, is indicated in patients with tumor lysis syndrome who develop severe hyperphosphatemia and renal failure with manifestations of uremia, volume overload, hyperkalemia, and acidosis. Turning over to hyperkalcemia related to malignancy, this can occur in 20% to 30% of patients with cancer. In particular, those with multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma, adult T-cell leukemia and lymphoma, as well as solid tumors like breast, renal, and lung cancer can be associated with hyperkalcemia. There are three mechanisms for hyperkalcemia. Most common is humoral hyperkalcemia, where you have the release of parathyroid hormone related protein, or PTHRP. In less than 20% of cases, hyperkalcemia is caused by osteolysis, or bone destruction, and in other settings, from extrarenal PTH-mediated 125-dihydroxyvitamin D production. Severe hyperkalcemia is defined as greater than or equal to 14 milligrams per deciliter. Hyperkalcemia can cause serious neurologic abnormalities, such as altered mental status and or coma, renal abnormalities, including polyuria and acute kidney injury, and cardiac manifestations, including bradycardia and short QT syndrome. The treatment of hyperkalcemia is volume expansion with isotonic saline at a rate of 250 cc per hour or greater. Diuretics are not routinely recommended and should be reserved for patients with hyperkalcemia who have signs of volume overload and congestive heart failure. Calcitonin, either subcutaneously or intramuscularly administered every 12 hours, can be effective for up to 72 hours. The standard of care for malignancy-related hyperkalcemia are the use of biphosphonates, which block bone resorption by osteocytes. They're efficacious and have a good safety profile. In particular, solidronic acid is preferred over pamidronate in patients with malignancy-associated hyperkalcemia who have normal to slightly impaired renal function. However, solidronic acid can be potentially nephrotoxic and can cause acute tubular necrosis and focal segmental glomerulosclerosis. Corticosteroids can be used for malignancy-associated hyperkalcemia that is mediated by ectopic PTH calcitriol activation. Hydrocortisone is commonly used, as you can see the dose there, for five days, followed by a seven-day taper of oral prednisone. Denusamab is a relatively new monoclonal antibody that is effective in patients with refractory malignancy-associated hyperkalcemia and can be a safe alternative to biphosphonates. It inhibits osteoclast maturation, function, and activation. However, it is not renally excreted and no dose adjustment is needed. You need to be aware, though, in giving denusamab that you can cause symptomatic hypokalcemia. Turning over to malignant spinal cord compression, this occurs in 5% to 10% of cancer patients with bone metastases, in particular with lung, breast, and prostate cancer, and less commonly with hematologic malignancies and renal cell carcinoma. Symptoms may include compressive indentation, displacement, or encasement of the thecal sac surrounding the spinal cord or cauda equina. The thoracic cord is usually the most common involved vertebra in 60% of cases. Symptoms include back pain, tenderness over the affected spinal region, motor weakness, sensory deficit, and autonomic dysfunction can occur. The diagnosis of spinal cord compression is made by magnetic resonance imaging of the total spine. And in patients where MRI is not feasible, CT myelogram can be used. Important treatment principles include pain control and preservation of neurologic function. Treatment of spinal cord compression includes the use of corticosteroids, such as dexamethasone, surgical decompression with neurosurgical involvement, as well as radiation therapy. Turning over to superior vena cava syndrome, 70% of SVC syndrome occurs from malignancy, usually from lung and or lymphomas. Resubstruction of blood flow in the SVC from extrinsic compression by enlarged nodes or by the tumor, or direct invasion of the tumor, or from devices such as central venous catheters or pacemakers. Typical manifestations include facial and upper extremity swelling, neck and superficial chest vein distension, dyspnea stridor, cough, and hoarseness. A widened mediastinum is seen on chest radiography. The diagnosis is typically made by contrast CT or MRI. Management includes airway stabilization, the use of corticosteroids for those with airway compression, thrombolysis, mechanical or pharmacologic, stenting of the SVC can be employed, systemic anticoagulation in those patients where a thrombus is present, keeping the head of the bed elevated, avoiding overhydration, caution with use of diuretics, and in select cases, radiotherapy and chemotherapy. Moving over to cardiac tamponade, this is commonly associated with metastatic lung and breast cancers, as well as lymphomas. Chest pain and dyspnea are clinical symptoms. Symptoms include hypotension, elevated jugular venous pressure, distant heart sounds, as well as pulsus paradoxus. ECG, as you can see on the top right, can be associated with low voltage, PR depression, and electrical alternates. An enlarged cardiac silhouette is seen on chest radiography. The imaging modality of choice for detecting cardiac tamponade is the use of transthoracic echocardiogram. Findings on echo include right atrial collapse, early diastolic collapse of the right ventricle, dilation of the IBC with absent normal inspiratory collapse. Management of cardiac tamponade will include echo, cardiography-guided pericardiocentesis, proper pericardial catheter drainage, creation of a pericardial window, and or pericardial sclerosis with chemotherapy. Turning over to malignant airway obstruction, the most common cause is primary bronchogenic carcinoma. You have external compression of the trachea or bronchi by the tumor or lymph node. In these patients, dyspnea is worse at night, and particularly when they're lying supine. They may have a productive cough, wheezing, and stridor, particularly if the obstruction is located in the trachea or the carina. The treatment of malignant airway obstruction includes rigid bronchoscopy with stenting, radiotherapy, or chemotherapy. Turning over to malignancy-related emergencies, first is blast crisis. Blast crisis is associated with the presence of 20% or more of peripheral or bone marrow blast cells, either of myeloid or lymphoid lineage. Approximately 10% of patients with CML will progress to accelerated phase and ultimately to blast crisis. Typical features include night sweats, fever, weight loss, symptoms of anemia, infection, and bleeding. Definitive management will largely depend on whether the patient has a myeloid or lymphoid leukemia. The most common cause of death in patients with CML who are in blast crisis is sepsis due to functional neutropenia. Hyperleukocytosis is defined as having a white blood cell count that's greater than 50 to 100,000 cells per microliter. Leukostasis is symptomatic hyperleukocytosis. It develops when the leukemic blasts aggregate in the microvasculature, commonly in the lungs, causing tissue hypoxia, thrombosis, or hemorrhage, even DIC, resulting in organ dysfunction or failure. Hyperleukocytosis can occur in 6 to 20% of adult AML patients. There's an abnormal interaction between the leukemic blasts and the endothelium with release of inflammatory cytokines like TNF and IL-1 beta. The lungs and the central nervous system are most commonly involved. The syndrome can be associated with leukocyte larceny, where you can have a spuriously low partial pressure of arterial oxygen, and therefore, you need to get pulse oximetry to record your oxygen saturation because that will be more accurate. The management of hyperleukocytosis with or without leukostasis will involve leukophoresis, particularly for those with acute myeloid leukemia, whose white blood cell count is greater than 50,000, and in ALL, if the white cell count is greater than 250,000. Neuroreduction with hydroxyurea or intensive chemotherapy is also indicated, and for patients with acute lung injury due to leukostasis from AML, corticosteroids, in particular dexamethasone, has proven to be efficacious. Hyperviscosity syndrome is another hematologic emergency that can occur in up to 15% of patients with Waldestrom macroglobulinemia, who have high levels of IgM plasma protein. Up to 6% of multiple myeloma can also develop hyperviscosity syndrome. This can present with headache, ataxia, seizures, or stroke, blurry vision or retinal hemorrhages, mucosal bleeding, as well as constitutional symptoms such as fatigue and malaise. The management of hyperviscosity syndrome is plasmapheresis, avoidance of transfusions until the hyperviscosity is reduced, and, of course, the use of chemotherapy and plobotomy to reduce viscosity. HLH, or hemophagocytic lymphohistocytosis, is a life-threatening hyperinflammatory syndrome that is seen not only with malignancies, but also with severe infections such as EBV or cytomegalovirus infection, autoimmune diseases, and after CAR T-cell therapy. It can occur after auto and allogeneic stem cell transplant associated with graft-versus-host disease. This syndrome can be associated with high mortality. The diagnostic criteria involves meeting at least five of the eight following criteria, including fever, spenomegaly, at least two cell lines that are cytopenic, hemophagocytosis in a specimen of bone marrow spleen, lymph node, or liver, high triglycerides, low fibrinogen, lower absent NK cell activity, very elevated ferritin levels, and elevated SIL2 receptor. The management for HLH include supportive transfusions. Since these patients are pancytopenic, they will need red blood cell transfusions. Platelet transfusions for those with coagulopathy or low fibrinogen plasma and cryoprecipitate will be indicated. These patients can mimic those with sepsis. It is very important that an infectious disease workup and management of appropriate infections with the right antibiotics is done. Control of blood pressure in patients that are hypertensive and the use of corticosteroids. Other treatments for HLH besides steroids might include Imapalumab, an interferon gamma monoclonal antibody, roxilitinib, cyclosporine, IVIG, anakinra, vincristine, varicitinib, siltuximab, as well as cytosol therapy. Turning over to immunotherapy-related toxicities, I will first discuss immune checkpoint inhibitors. There have been at least 10 FDA-approved checkpoint inhibitors over the past decade. These checkpoint inhibitors typically target either cytotoxic delymphocyte antigen 4, or CTLA-4, or PD-1, program death 1, or PD-L1, program death ligand 1. They are indicated in a variety of solid tumors, such as metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, urethereal cancer, but have also been found useful in selected cases of Hodgkin's lymphoma, as well as melanoma. Neurotoxicity, pulmonary toxicity, and other toxicities have been associated with these checkpoint inhibitors. In terms of neurotoxicity, posterior reversible encephalopathy syndrome, or PRESS, along with myelitis and peripheral neurotoxicity that may look like Guillain-Barre syndrome or myasthenia gravis. You can get encephalitis and even seizures in some patients. Pulmonary toxicity usually takes the form of pneumonitis, and in terms of other toxicities, checkpoint inhibitors can also be associated with endocrinopathies, such as hypophysitis, adrenal or thyroid dysfunction. Myocarditis is an important adverse side effect of checkpoint inhibitors. They can also get pericarditis, hepatotoxicity, interstitial nephritis, liver dysfunction, and as well as dysrhythmias. Management of checkpoint inhibitor toxicities, again, is with corticosteroids, and for those cases where corticosteroids may not be sufficient or patients are refractory to steroids, the use of infliximab, mycophenolate, antithymoside globulin, tocilizumab, rituximab, IVIG, and plasmapheresis may also be indicated. Finally, with regards to chimeric antigen receptor or CAR T cell therapy toxicities, there are at least six important ones. The two most common are cytokine release syndrome, or CRS, and neurologic or immune effector cell-associated neurotoxicity syndrome, or ICANS. Secondary HLH may also occur. Grade III or IV cytopenias are common and persist beyond 30 days. Tumor lysis syndrome can also occur. These patients develop B-cell aplasia and may need lifelong treatment with IVIG because of low gamma globulin levels. CRS, or cytokine release syndrome, is a hyperinflammatory syndrome following CAR T cell therapy, mediated by IL-6 and IL-1. It can range in incidence from 37% to 93% for those with lymphoma, and 77% to 93% for those with leukemia. CRS is most common in patients with high disease burden, high CAR T cell therapy, and high CAR T cell doses, and those that receive fludarabine-based lymphodepleting chemotherapy. Symptoms are gradual in onset. They start usually within the first seven days after CAR T cell infusion. Laboratory findings are variable. Elevated CRP, ferritin, and IL-6 are common, as well as TLS-related derangements, such as high potassium, high phosphorus, and low calcium. The grading of CRS has been standardized by the American Society for T-cell Therapeutics. They include the presence of fever, cardiac depression, i.e., hypotension, as well as respiratory symptoms, such as hypoxia. Fever is present in all grades. Grading is from grade one to four. Cardiac three and four manifestations include hypotension, shock requiring one or multiple pressures. Cardiomyopathy may occur, as well as life-threatening arrhythmias. Respiratory manifestations in grade three or four typically are hypoxemia requiring either high-flow nasal cannula or noninvasive positive pressure or mechanical ventilation. So patients with at least grade two, and certainly those with grade three and four CRS, are patients that will require admission to the ICU. Management of CRS, again, depends on the grade. For those with grade one CRS, it's usually supportive with treatment with antipyretics for the fevers, intravenous fluid hydration, sepsis workup, imaging, and appropriate empiric antibiotic therapy. For those with grade two CRS, again, besides increasing the monitoring of vital signs and ICU admission, tocilizumab, IL-6 inhibitor, or siltuximab, an IL-6 receptor blocker may be used in these patients. And for those who have grade three or four that are in the ICU, besides tocilizumab or siltuximab, corticosteroids such as dexamethasone may be used in increasing doses, including up to pulse doses of steroids if indicated, like methylprednisolone, one gram daily IV for three days. Tocilizumab is usually dosed at eight milligrams per kilogram, with a total dose not exceeding 800 milligrams. In refractory cases, siltuximab, anakinra, and pulse steroids are commonly indicated for severe CRS. For ICANs or neurologic toxicity, this is usually related to a breakdown in the integrity of the blood-brain barrier, where you have leukocyte and cytokine infiltration into the CSF. This usually occurs four to five days after CAR T cell therapy, with antecedent severe CRS as a primary risk factor. Other risk factors include history of neurologic disease, high tumor burden, high CAR T cell dose, as well as receipt of CD28 co-stimulated CAR T cell products in those patients with an abnormal brain MRI. Manifestations and lab markers can include elevated CRP, cytokine levels such as IL-6, IL-10, IL-12, IL-15, and the presence of encephalopathy, headache, abdondation, somnolence, aphasia, tremor, and in some patients, the development of seizures and even coma. Grading, just like with CRS, is from grade one to four. It includes assessment of an encephalopathy score or the eye score, level of consciousness, the presence or absence of seizures, cerebral edema or high intracranial pressure, and abnormal motor findings. For those with grade three or four, these are, again, patients that will most likely be in the ICU. These are patients who have depressed mentation. They may have a partial seizure, convulsive seizure, or maybe even in status epilepticus. They may have focal local edema on imaging or diffuse cerebral edema, or they may have in grade four severe motor findings or motor deficits such as hemiparesis or even paraparesis. This is the eye score that's assessed at the bedside involving orientation, the ability of the patient to name objects, follow commands, writing simple sentences, and attention span. Management for grade one and two is supportive with intravenous hydration and aspiration precautions, EEG to rule out seizures, and brain imaging to rule out cerebral edema and the use of high-dose thiamine. Prophylactic anti-seizure medications such as with levothyracetam may be started on the day of CAR T-cell infusion in patients that are receiving CAR T-cell products that are known to be associated with a high incidence of neurotoxicity. Tocilizumab should only be used in patients with eye cans who also have concurrent CRS. For grades three and four, steroids such as dexamethasone plus anakinra and or methylprednisolone in pulse doses may be used. Patients may require intubation and mechanical ventilation for airway protection, seizure control, and for those with cerebral edema, high-dose steroids and measures to lower ICP such as hyperventilation, hyposmolar therapy, and even neurosurgical consultation for possible VP shunt may be indicated. In summary, oncologic emergencies can be metabolic, structural, cardiopulmonary, malignancy related, and immunotherapy related. Prompt recognition and institution of appropriate therapy can be life-saving, and as intensivists, we need to have a working knowledge of the diagnosis and management of classic and novel immunotherapy-related toxicities. Thank you.

oncologic emergencies

tumor lysis syndrome

hypercalcemia

hematologic malignancies

cancer immunotherapies

cytokine release syndrome

spinal cord compression