An oncologic emergency can be broadly defined as any complication related to cancer or anticancer therapy that requires immediate intervention. While some complications are insidious and may take weeks or months to develop, others manifest in a few hours and quickly lead to severe outcomesincluding paralysis, coma, and death 1. Despite the increasing incidence of cancer in the general population, cancer mortality rates are dropping due to rapid advances in treatment. The improvement in long-term survival of patients with cancer -combined with increasing use of more efficient outpatient treatment strategies -contribute to the likelihood that acute care providers will encounter oncologic emergencies in their practices more regularly 2,3. The information below summarizes the most common oncologic emergencies one will likely encounter in the adult population.
Guideline Questions 1. What are the most common oncologic emergencies an acute care physician is likely to encounter? 2. What are the recommended management strategies for these emergencies?

# Target Population
The following recommendations and management strategies apply to adult patients who are currently being treated for cancer. Different principles may apply to pediatric and elderly patients.

# Search Strategy
For the 2022 guideline update, medical journal articles were searched using the PubMed database (publication date 2014 to 2019), and the references and bibliographies of articles identified through this search were scanned for additional sources. Articles were excluded from the final review if they had a non-English abstract, involved only pediatric or elderly patients, were a case report, or were published prior to January 2014.  Patient can be placed into lateral decubitus (on the bleeding side) if side of bleeding is known.  Selective intubation with regular endotracheal tube into the non-bleeding side, which might require help with fiberoptic guidance. Avoid double lumen tube. o Use of nebulized tranexamic acid 500 mg TID. o Arrange transfer to a centre with surgical and radiotherapy resources.

# Summary of Recommendations
- Gastrointestinal (GI) Bleeding (overt)
- Control vomiting/retching. o If gastric or duodenal source pantoprazole infusion (80 mg bolus, then 8mg/h). o If esophageal variceal sourceoctreotide infusion (50 g bolus, then 50 g/h). o Consult a Gastroenterologist for definitive management. - Hematuria o Light bleeding: pink or cranberry juice, transparent, no clots or limited tiny clots, and patient is not in retention.  Encourage patient to drink fluids to dilute urine and refer to outpatient Urology. - Dexamethasone (10mg IV followed by 4-8mg/dose, q6h IV or PO) and consider consultation with Neurosurgery. - Administer anticonvulsant therapy with a short-acting benzodiazepine (midazolam 2mg or lorazepam 1mg IV) to halt seizure activity. - Loading dose of phenytoin 15 mg/kg followed by a daily dose of 300 mg/d can be considered but consult Neurology for specific advice.

# Malignant Airway Obstruction:
- Administer corticosteroids: Dexamethasone (10mg IV followed by 4-8mg/dose, q6h IV or PO) as quickly as possible. - Administer Heliox: if patient has stridor and is not hypoxemic (21% oxygen, 79% helium-up to 30% oxygen, 70% helium). - Contact Thoracic Surgery or Interventional Pulmonary immediately and/or arrange transfer to a center with these resources available. Superior Vena Cava Obstruction:
- Administer corticosteroids: Dexamethasone (10mg IV followed by 4-8mg/dose, q6h IV or PO) daily. - Arrange transfer to a centre with surgery and radiotherapy resources.

# Spinal Cord Compression:
- Administer corticosteroids: Dexamethasone (10mg IV followed by 4-8mg/dose, q6h IV or PO).
- Consult Spine Service for surgical opinion.

# Systemic Emergencies
- Panculture (blood/urine) and immediate antibiotic therapy with broad-spectrum antibiotics, eg: piperacillin-tazobactam 4.5 grams IV q8h (renal adjustment required) OR cefepime monotherapy: 2g IV q8h.

# Hypercalcemia (Malignancy Associated):
- Fluid resuscitation with IV normal saline (250-500 mL/hour) + IV bisphosphonates (pamidronate 15-90 mg over 1-2 hours OR zoledronate 4mg over 15-30 minutes). - May add calcitonin for severe hypercalcemia (IM/SC 4-8 units/kg q6h x2d). Hyperviscosity Syndrome:
- Avoid transfusions if possible.
- Perform phlebotomy (remove 100-200mL whole blood) with hydration (500-1000mL of normal saline). - Consult Hematologist for access to plasmapheresis (requires transfer to tertiary care center with apheresis capabilities). Checkpoint Inhibitor Related Toxicities:
- Consult the Checkpoint Inhibitor prescribing physician. Syndrome of Inappropriate Antidiuretic Hormone Secretion -Severe Hyponatremia:
- Acute duration: Fluid restrict (1L /day).
- Hyponatremic encephalopathy: administer IV hypertonic saline (100mL 3 % IV over 10 minutes with 1-2 repeat boluses as needed to increase plasma sodium by 4-6mEq/L). - Chronic duration: Restrict fluids (1L /day). If no change after 24-38 hours: consider furosemide (20-40 mf IV or 20-80 mg orally daily) OR demeclocycline (600-1,200 mg/day orally in 3 or 4 divided doses). Tumour Lysis Syndrome:
- Administer IV saline (250cc/hour or more), + rasburicase (6mg given as a 30 min infusion). o Avoid rasburicase in patients with known glucose-6-phosphate dehydrogenase (G6PD) deficiency; use allopurinol (100 mg/m 2 q8h to maximum 800 mg per day) for these patients. - Refer to tertiary centre for additional management and possible dialysis.

# Recommendations and Discussion: Single System Emergencies
Management of oncologic emergencies should include communication with the patient or alternate decision maker about treatment benefits and drawbacks, with respect to disease status and goals of care.

# Hemorrhage/ Bleeding
Acute bleeding in patients with cancer can be due to the underlying malignancy, antineoplastic therapy, or non-malignancy related factors. The most common presentations are DIC, hemoptysis, overt gastrointestinal (GI) bleeding, and hematuria.
- General Bleeding Recommendations: o In any bleeding patient, basic investigations should include complete blood count (CBC), blood smear, prothrombin time (PT-INR), activated partial thromboplastin time (aPTT), D-dimer and fibrinogen level 4. o Management initial steps: Transfuse Packed Red Blood Cells (PRBCs), correct any coagulopathy with Fresh Frozen Plasma (FFP 15-30 mL/kg)  platelets (a reasonable target is 50 x10 9 /L) as needed .

# Disseminated intravascular coagulation (DIC):
DIC is an abnormal bleeding and clotting cascade due to inappropriate thrombin activation. It causes rapid formation of fibrin clots in the microcoagulation, consumption of clotting factors, and clot degradation 5,9. Continuous bleeding and clotting then continues until clotting factors are completely consumed -this can manifest as uncontrollable bleeding.
- Etiology. o Most commonly seen with acute promyelocytic leukemia, mucin-producing solid tumours (pancreatic, gastric, ovarian, breast) and brain tumours 4,5,7,9. - Presentation.
- Can present with bleeding, thrombosis or both 7,10. o Malignancy-associated DIC is usually more subacute than that seen in sepsis/trauma.
Hemoptysis is the most immediate life-threatening symptom of progressive intrathoracic disease 12.
Life-threatening hemoptysis (the expectoration of 250mL-600mL of blood over 24 hours) can lead to asphyxiation or exsanguination 13.
- Etiology. o In cancer patients, the primary causes are malignancy, infection, and hemostatic abnormalities 12,13. o Bronchogenic carcinoma is the most common cause of life-threatening hemoptysis in cancer patients over 40 years of age 13 ; lung metastases from primary melanoma, breast, kidney, laryngeal and colon cancers are another common cause 13. o Other factors contributing to increased risk of hemorrhage include thrombocytopenia, coagulopathy (due to either the malignancy itself or its treatment) and radiation-or chemotherapy-induced lung damage 13. - Presentation.
- Symptom severity is dependent on the rate and duration of bleeding, the degree of airway obstruction and pulmonary involvement, and the patient's underlying performance status and concurrent comorbidities 13. o In addition to hemoptysis, patients may be hypotensive, tachycardic, centrally cyanotic and clammy, and may experience dyspnea or chest pain from underperfusion 13. - Diagnosis.
- Initial diagnostic efforts will often need to occur simultaneously with management 14.  Chest radiography and routine laboratories.  Rigid bronchoscopy (expertise required, can be performed bedside in unstable patient).  Bronchoscopy and chest computed tomography (CT) ideally performed within first 12-14 hours. - Management.
- Protect the airway: Intubation is warranted with rapid bleeding, hemodynamic instability, ventilatory impairment, severe dyspnea or hypoxia 13,14.
Hemoptysis Management Summary:
Protect airway, correct underlying coagulopathies, suppress cough as needed; patient can be placed into lateral decubitus (on bleeding side) if side of bleeding is known; selective intubation with regular endotracheal tube into non-bleeding side (might require fiberoptic guidance); avoid double lumen tube; arrange transfer to a centre with surgical and radiotherapy resources.
 Patient can be placed into lateral decubitus (on the bleeding side) if side of bleeding is known.  Selective intubation with regular endotracheal tube into the non-bleeding side, which might require help with fiberoptic guidance. Avoid double lumen tube. o see General Bleeding Management o Use of nebulized tranexamic acid 500 mg TID 15 o Admit to Intensive Care Unit (ICU) if appropriate.

# GI bleeding (overt):
- Etiology. o Upper GI bleeding is most commonly caused by primary upper GI malignancies and common non-malignancy related GI pathology.  Less commonly, it is related to metastases to the esophagus, stomach, or duodenum, lymph node disease with invasion of overlying mucosa, and mucositis secondary to chemotherapy 16. o Lower GI bleeding can be from primary GI malignancies, non-malignancy related GI pathology and indirectly by various cancer therapies (e.g., graft-versus-host disease following stem cell transplantation, radiation-induced proctosigmoiditis, etc.) 16.

# - Presentation.
- Upper GI bleeding typically presents with hematemesis and/or melena 16. o Appearance of lower GI bleeding depends on the briskness of hemorrhage and speed of heme passage through the GI tract 16 but can range from frank red blood per rectum to melena. o Attempting to identify the site of bleeding by the characteristics of the stool is imprecise.
- Obtain information on: nature/duration of bleeding, nature of any recent emesis, stool habits, bleeding diatheses, prior GI bleeding, history of pharmaceutical anticoagulation, NSAID use, chemo-and radiotherapy treatments, history of comorbid conditions that may impact evaluation or treatment decisions 16,17. o Collect essential labs (CBC, chemistry panel, coagulation panel, liver function tests, blood type and crossmatch) 16. o NG aspiration with lavage may help confirm the source and briskness of bleeding 16
. - Management.
- Initial management should focus on 16 :  Rapid assessment of airway, breathing and circulation.  See General Bleeding Management.
- Control vomiting and retching 16.

# GI Bleeding Management Summary:
Control vomiting/retching; gastric or duodenal source pantoprazole infusion (80mg bolus, then 8mg/h); esophageal variceal source octreotide infusion (50g bolus, then 50g/h); consult a Gastroenterologist for definitive management.
- For bleeds that are suspicious for a gastric or duodenal source, a pantoprazole infusion (80mg bolus, then 8mg/h) should be started. o For bleeds that are suspicious for an esophageal variceal source, an octreotide infusion (50g bolus, then 50 g/h) should be started 16,18. o Refer to a Gastroenterologist for definitive management (e.g., endoscopy, radionuclide scintigraphy, selective angiography, and embolization) 16,17,19.
- Etiology. o Urothelial carcinoma, renal cell carcinoma and metastases to the kidney, prostate cancer, urethral or vascular invasion of penile cancers, previous instrumentation/ catheter trauma, radiation cystitis (related to pelvic irradiation) 20,21. - Presentation.
- The appearance of bleeding can assist in determining its origin:  Long, worm like clots usually indicate upper tract bleeding 22.  Bright red blood without clots that partially clears during urination usually indicates a lower tract bleed, as do broader clots (less common), which can be difficult to evacuate 22. o Light bleeding: pink or cranberry juice, transparent, no clots or limited tiny clots, and patient is not in retention. o Heavy bleeding: thick/opaque hematuria and/or large clots and/or clot retention.
- Complete history and physical exam 22.  29.  Other common primary tumours include colorectal cancer and renal cell carcinoma 30,31.  Melanoma and lung cancer are most frequently associated with multiple brain metastases, whereas breast, colorectal, and renal cancers are more likely to be associated with a solitary metastasis 32.

# - Presentation:
- Patients with brain metastases may experience a variety of neurological symptoms, the most common of which is subacute onset of headache -this occurs in approximately 50% of cases. o Other common symptoms include hemiparesis, altered mental status, impaired cognition, increased intracranial pressure, and seizures 29,32. o Increased intracranial pressure and seizures lasting longer than 30 minutes (status epilecticus) are considered oncologic emergencies.

# - Diagnosis:
- Contrast enhanced MRI is the preferred diagnostic tool 32.  CT can be used but is less sensitive.

# - Management:
- Treat elevated intracranial pressure initially with dexamethasone (10mg IV followed by 4-8mg/dose, q6h IV or PO) and consider consultation with Neurosurgery). o Administer anticonvulsant therapy with a short-acting benzodiazepine to halt seizure activity (midazolam 2mg or lorazepam 1mg IV). o No current trials establishing 1 medication over another 33.
Brain Mets Management Summary: Dexamethasone (10mg IV followed by 4-8mg/dose, q6h IV or PO) and consider consultation with Neurosurgery; Administer anticonvulsant therapy with a short-acting benzodiazepine (midazolam 2mg or lorazepam 1mg IV) to halt seizure activity; Loading dose of phenytoin (15mg/kg followed by a daily dose of 300mg/d) can be considered but consult Neurology for specific advice.
- Loading dose of phenytoin (15mg/kg followed by a daily dose of 300mg/d) can be considered but consult Neurology for specific advice o For more information, see Cancer Care Alberta's Brain Mets Guideline 34.

# Malignant Upper Airway Obstruction
Airway obstruction in patients with cancer is caused by tumour encroachment and by tumourassociated airway edema or hemorrhage 13.
- Etiology: o Most commonly related to direct extension from an adjacent tumour (usually inoperable or recurrent) in the mediastinum (i.e. lung cancer, thymoma), or a primary head and neck tumour 35. o Less commonly from local extension of metastatic tumour from esophageal, thyroid, breast, or renal primaries 32,35.

# - Presentation:
- Symptoms of malignancy-associated airway obstruction are not specific to malignancy; it is critical that the provider consider this diagnosis in their differential for this presentation.
 The most common presenting symptoms include dyspnea, hemoptysis, wheezing, hoarseness, difficulty clearing secretions, and cough 32,35,36.  Stridor is also a common presenting complaint; the effect is most marked on inspiration, and can progress to a near-complete obstruction as a result of infection, inflammation, or manipulation of the airway 36.  Progressive symptoms represent a true medical emergency.
- For most patients, the physical examination (which may be aided by direct visualization with a laryngoscope or bronchoscope) is sufficient for diagnosis -depending on the location of the lesion 13. o A CT scan or x-ray 37 of the neck and chest is the best initial study to assess the location and extent of the obstruction 36 if the patient can tolerate lying flat.

# - Management:
- Use dexamethasone immediately upon diagnosis (10mg IV followed by regular doses q6h, 4-8mg IV) o Administer Heliox: if patient has stridor and is not hypoxemic (21% oxygen, 79% heliumup to 30% oxygen, 70% helium) o Laryngoscopy or bronchoscopy may be necessary to guide the placement of an endotracheal tube 13.
Airway Obstruction Management Summary:
Administer dexamethasone as soon as possible (10mg IV followed by 4-8mg/dose, q6h IV or PO); Administer Heliox: if patient has stridor and is not hypoxemic (21% oxygen, 79% helium); Contact Thoracic Surgery or Interventional Pulmonary immediately and/or arrange transfer to a center with these resources available.
- Rigid bronchoscopy provides the safest and most effective means of immediate airway control and initial stabilization; Interventional Pulmonary Medicine is on call 24 hours/7 days a week at specific centres. o Consult surgical services urgently if there is concern that the above measures are insufficient, and a surgical airway will be required. o Contact Thoracic Surgery or Interventional Pulmonary immediately and/or arrange transfer to a center with these resources available.

# Superior Vena Cava Obstruction
Superior vena cava obstruction (SVCO) results from partial or complete obstruction of blood flow from the superior vena cava to the right atrium. The obstruction may be caused by vessel compression, invasion, thrombosis, or fibrosis 13.
- Etiology: o Both lung cancer (small cell and non-small cell) and non-Hodgkin lymphoma account for approximately 85% of SVCO cases 38.  Approximately 10% of patients with small cell lung cancer, 2-4% of patients with non-small cell lung cancer, and 2-4% of patients with non-Hodgkin lymphoma will develop SVCO at some point during their disease course 38,39. o An increasing number of cases of SVCO in cancer patients are also due to thrombosis of indwelling central venous catheter devices and/or pacemaker leads 32,38,40.

# - Presentation:
- Symptoms:  The most common are facial or neck swelling, arm swelling, and dilated chest vessels 2,38.  Cough, dyspnea, and orthopnea are also common symptoms that can often mimic congestive heart failure or pericardial disease 41.  Worrisome signs include: stridor, which may indicate laryngeal edema, and headache or confusion, which may indicate cerebral edema 38. o Sudden onset of SVCO causes rapid elevation of pressure in the superior vena cava, resulting in increased intracranial pressure and cerebral edema, intracranial thrombosis or bleeding, and even death 13. - Diagnosis:
- Accurate diagnosis via imaging should always be obtained.  A contrast-enhanced CT scan of the chest wall is the most useful study, as it clearly identifies the level and extent of the blockage, and delineates collateral drainage pathways 38.  MRI is useful for patients who cannot tolerate the contrast medium 38,42.

# SVCO Management Summary:
Administer dexamethasone (10mg IV followed by 4-8mg/dose, q6h IV or PO); Arrange transfer to a centre with surgery and radiotherapy resources.
 Venography is generally only warranted when an intervention such as stent placement or surgery is planned 42. o If a patient presents with SVCO without a prior diagnosis of malignancy, every effort should be made to obtain biopsies and histologic diagnosis after patient stabilization 32.  This aids the decision on whether curative versus palliative treatment is most appropriate 38. - Management:
- Acute management involves securing the airway and administering corticosteroids  Dexamethasone 10mg IV followed by 4-8mg/dose, q6h IV or PO  Transfer to a center with surgery and radiotherapy resources.
- Definitive management is guided by the severity of the symptoms and the underlying malignancy, as well as by the anticipated response to the treatment .  For more information, refer to Cancer Care Alberta's Palliative Radiotherapy: Superior Vena Cava Obstruction guideline 45.

# Spinal Cord Compression
Malignant epidural spinal cord compression (SCC) is a common complication that affects approximately 5%-10% of all adult patients with cancer, and most commonly occurs in the setting of widespread metastatic disease 28. The most common site of cord compression is in the thoracic spine (60% of cases), followed by the lumbosacral spine (25% of cases), and finally the cervical spine (15% of cases). Multiple sites of spinal cord compression also occur in up to 35% of patients 46.

# SCC Management Summary:
Administer dexamethasone 10mg IV followed by 4-8mg/dose, q6h IV or PO; Consult Spine Service for surgical opinion.
- Management: o Corticosteroids should be administered as soon as SCC is suspected or confirmed, as the most important prognostic indicator for ambulatory outcome is pre-treatment motor function 32,48.  Dexamethasone rapidly reduces spinal cord edema and back pain and may also improve neurologic functioning 28,32,.  The typical dose of dexamethasone is 10mg IV followed by 4-8mg/dose, q6h IV or PO. o The Spinal Service should also be consulted for a surgical opinion.
 For more information, refer to Cancer Care Alberta's Palliative Radiotherapy: Bone Metastases and Spinal Cord Compression guideline 52.

# Recommendations and Discussion: Systemic Emergencies

# Febrile Neutropenia
Febrile neutropenia is one of the most common complications related to systemic cancer therapy and is considered a potentially life-threatening medical and oncologic emergency.
Spontaneous bacterial infection can occur in the setting of severe neutropenia (neutrophils less than 0.5x10 9 /L). The primary source of pathogens is the patient's endogenous flora 53. The mortality rate associated with febrile neutropenia in patients with cancer is between 5 and 20%; therefore, timely recognition of symptoms and administration of antibiotics is critical for the prevention of sepsis and death 54,55.
- Presentation: o Fever higher than 38.3C OR higher than 38.0C for more than 1 hour, in a patient who has received systemic cancer therapy in the past month AND has an absolute neutrophil count (ANC) less than 0.5 x 10 9 cells/L 56,57  o Provide initial antibiotic therapy with piperacillin-tazobactam 4.5g IV q8h (renal adjustment required) OR cefepime monotherapy: 2g IV q8h, plus IV fluids 58. o For more information see Cancer Care Alberta's Febrile Neutropenia Guideline 58.

# Febrile Neutropenia Management Summary:
Panculture (blood/urine) and immediate antibiotic therapy with broad-spectrum antibiotics, e.g.: piperacillin-tazobactam 4.5g IV q8h (renal adjustment required) OR cefepime monotherapy: 2g IV q8h.

# Malignancy Associated Hypercalcemia
Hypercalcemia is defined as a corrected serum calcium > 2.6 mmol/L 3,59. Note: While unexpected hypercalcemia of unknown etiology may be an indicator of malignancy, the information that follows focuses on the identification and management of hypercalcemia in the patient already known to have cancer. Corrected values are approximations and may not be precise or reliable. Serum ionized Ca 2+ should be measured when the validity of measured total calcium is in doubt .
- Malignancy-associated hypercalcemia (MAH) occurs in up to 30% of patients with cancer.  Most commonly in those with solid breast, lung, head/neck tumours, and hematologic malignancies (especially multiple myeloma and adult T-cell leukemia/lymphoma) . o Humoral hypercalcemia accounts for the majority of MAH cases (80%) 3,62. o Osteolytic bone metastases account for the other 20% of MAH cases; other causes (such as ectopic PTH secretion, vitamin D secreting lymphomas, etc.) account for less than 1% 3,62. o Many cancer therapies (e.g., antineoplastic agents, vitamin D analogues) can also induce or exacerbate hypercalcemia, particularly when therapies are combined 60.

# - Presentation and Diagnosis:
- Mild hypercalcemia may be asymptomatic and does not require therapy. o Moderate to severe hypercalcemia is typically symptomatic (see below) 3,59,60,63 and requires therapy:

# Hyperviscosity Syndrome
Hyperviscosity syndrome refers to symptoms from increases in blood viscosity, which then decrease tissue perfusion. Causes of elevated viscosity include increased protein content, large molecular size, abnormal polymerization, and abnormal shape of immunoglobulin molecules 66.
- Etiology: o Hyperviscosity syndrome can occur secondary to a variety of hematologic malignancies.  The most common is Waldenstrom macroglobulinemia, which accounts for up to 80% of cases 67.  Waldenstrom macroglobulinemia is a relatively rare lymphoma that produces a monoclonal immunoglobulin M (IgM) protein 68. o Less frequently, hyperviscosity syndrome may occur in patients with multiple myeloma (also from very high monoclonal protein production) or from hyperleukostasis in acute leukemia or erythrocytosis from polycythemia 66,69.

# - Presentation:
- The triad of bleeding, visual disturbances, and/or focal neurologic signs 70.  Bleeding typically arises from mucosal sites, most commonly occur in the lining of the nose, gums, the retina and the lumen of the gastrointestinal tract and the surface of the brain .  Visual changes may manifest as diplopia, blurred vision and are associated with papilledema and retinal hemorrhages or thrombosis 71.
- Fundoscopic examination commonly reveals dilation or engorgement of retinal veins, resembling the appearance of "sausage links" 69,70.  Neurologic manifestations often include headache, dizziness, vertigo, ataxia, encephalopathy, hearing impairment, seizures, somnolence, cerebral hemorrhage, and altered mental status . o Hyponatremia and hypercalcemia may also be present 32   There is no linear relationship between serum viscosity and the appearance of hyperviscosity symptoms 32.  Asymptomatic patients with an elevation in the serum viscosity do not require treatment 71.
Hyperviscosity Management Summary:
Avoid transfusions if possible; Perform phlebotomy (remove 100-200mL whole blood) with hydration (500-1000mL of normal saline); Consult Hematologist.
- Additional laboratory evaluations such as an electrolyte panel, peripheral blood smears, measurement of quantitative Ig levels, and imaging studies should be used to rule out other causes of the presenting symptoms. - Management:
- Short-term management is directed at immediately reducing blood viscosity -most effectively accomplished via plasmapheresis. o If the patient presents with severe neurologic symptoms (seizures or coma), or plasmaphresis is not readily available -phlebotomy of 100 to 200mL of whole blood can also be used to rapidly reduce acute symptoms 32,69,73 (and may be aided by hydration post-phlebotomy -ex 150cc/hr to 500-1000mL).

# Checkpoint Inhibitor Related Toxicities
Immune checkpoint inhibitors (CPIs) are antibodies that increase anti-tumour activity by inhibiting natural regulators of immunity. By modulating the activity of the immune system, CPIs can cause inflammatory side effects called immune-related adverse events (irAEs) that present like new auto-immune disorders 74. irAEs are toxicities caused by non-specific activation of the immune system.
- CPIs are currently approved in the setting of melanoma, non-small cell lung cancer, renal cell cancer and bladder cancer 75. - Common irAEs include dermatitis, colitis/diarrhea, hepatitis and arthritis.
- Immune-related endocrinopathies may occur with CPI treatment, including thyroiditis (and associated hyper and hypothyroidism), hypophysitis (and associated secondary adrenal insufficiency) and diabetes. - Serious irAEs suchas pneumonitis or myocarditis are rare but may be life threatening.
- For more information please see CCA's guideline on Follow-up and Management of Checkpoint Inhibitor Related Toxicities in Cancer Patients 74.

# Syndrome of Inappropriate Antidiuretic Hormone Secretion -Severe Hyponatremia
Syndrome of inappropriate antidiuretic hormone (SIADH) results from the inappropriate production and secretion of antidiuretic hormone (ADH, also known as arginine vasopressin or AVP) which leads to water retention/intoxication, hyponatremia and hypoosmolality 76.
CPI Related Toxicities Management Summary:
Consult with the CPI prescribing physician; online guidance is available in emergent situations.

# SIADH Management Summary:
Acute duration: Fluid restrict (1L/day); Hyponatremic encephalopathy: administer IV hypertonic saline (100mL 3 % IV over 10 minutes with 1-2 repeat boluses as needed to increase plasma sodium by 4-6 mEq/L). o In cancer patients, SIADH can be caused by:  The ectopic production of ADH by tumour tissue 76,77.
- Most common: small cell lung cancer  The inappropriate production and release of ADH from the posterior pituitary gland 76,77.  Cytotoxic chemotherapy and other pharmacologic agents.
- Opioid analgesics, tricyclic antidepressants, and selective serotonin reuptake inhibitors can also increase ADH production. - NSAIDs, thiazide diuretics, barbiturates and anesthetic agents can increase the effects of ADH on the renal tubules 76.

# - Presentation:
- Despite the water intoxication caused by SIADH, signs and symptoms of fluid overload (hypertension, peripheral edema, ascites, heart failure) are rarely observed as much of the excess water diffuses into intracellular fluid -only a portion is retained in the intravascular and interstitial spaces 76. o The main symptoms are neurological dysfunction secondary to water intoxication that leads to swelling of the brain cells. - Slow correction recommended to avoid osmotic demyelination 78,82.

# Tumour Lysis Syndrome
Tumour lysis syndrome (TLS) is a complication of cellular breakdown in rapidly proliferating, bulky, or highly chemo-radiosensitive tumoursand the subsequent release of intracellular contents into the bloodstream 84,85. TLS is characterized by hyperuricemia and major electrolyte disturbances (hyperkalemia, hyperphosphatemia and hypocalcemia) 85,86. Without timely intervention, TLS can lead to oliguric renal failure, seizures, cardiac arrhythmias, and death 84,85.
- Etiology: o Most frequently occurs in hematologic malignancies, and very rare in solid tumours 86,87.

# TLS Management Summary:
Administer IV saline (250cc/hour or more), + rasburicase (6mg given as a 30-min infusion); Avoid rasburicase in patients with known G6PD deficiency; use allopurinol (100 mg/m2 q8h to maximum 800 mg per day) for these patients; Refer to tertiary centre for additional management and possible dialysis.
 TLS can rarely occur spontaneously in highly proliferative diseases (Burkitt Lymphoma or Acute Lymphoblastic Leukemia) but is usually triggered by therapy and occurs early (within days) of treatment initiation/change in therapy.

# - Diagnosis:
- TLS is often divided into laboratory TLS and clinical TLS. o Laboratory TLS can be defined by: 2 or more of the following metabolic abnormalities that arise within 7 days after the initiation of chemotherapy 88 :  serum uric acid >476mol/L (or 25% increase from baseline)  serum potassium 6.0mmol/L (or 25% increase)  serum phosphorous 1.45mmol/L in adults (or 25% increase)  hypocalcemia (serum calcium 1.75mmol/L or 25% decrease)
- Clinical manifestations of TLS are variable and may include nausea, vomiting, decreased urine output, renal failure, fluid overload, congestive heart failure, arrhythmias, lethargy, paresthesias, muscle cramps, tetany, syncope, seizures, and sudden death 85,88. o In patients with obstructive uropathy secondary to hyperuricemia-hematuria, flank or back pain and hypertension may be present 85.

# - Management:
- Aggressive hydration with normal saline should immediately be initiated for suspected TLS (250cc/hour or more). o If TLS is confirmed, rasburicase 6mg IV as a 30min infusion should be provided to reduce the uric acid and prevent further renal injury (usually requires transfer to a tertiary care centre). o Avoid rasburicase in patients with known glucose-6-phosphate dehydrogenase (G6PD) deficiency.  Use allopurinol (100 mg/m 2 q8h to maximum 800 mg per day).
- Severe or worsening TLS may warrant hemodialysis so urgent transfer to a dialysis centre should be organized. - Specific management strategies for TLS laboratory abnormalities:
- Hyperuricemia.  Rasburicase 6mg IV as a 30 min infusion is recommended for treatment of TLS.
- Avoid rasburicase in patients with G6PD deficiency, use allopurinol (100 mg/m 2 q8h to maximum 800 mg per day) in these patients 89,90.
 For severe hyperkalemia, rapid acting insulin and a dextrose infusion should be administered 90.
- Recommended dose is regular insulin (10 units) IV plus 100mL of a 50% dextrose solution (D50). - May be repeated after 30-60 minutes (monitor finger prick glucose closely).
 Calcium gluconate via slow infusion (and with continuous ECG monitoring for bradycardia) may be used for life-threatening arrhythmias 85,.
- Recommended dose is 1g (10 mL of 10 percent solution).  Sodium bicarbonate can be given IV push to induce the influx of potassium (K) into cells, in addition to the above treatments if patient is acidemic.
- Should not be administered in same line as calcium solutions.
- Recommended dose 45-50mEq slow IV infusion over 5-20 minutes 90.  Albuterol can also be used to help shift potassium into the intracellular space.
- Recommended dose 10-20mg in 4mL saline nebulized over 20 minutes or 10 to 20 puffs per metered dose inhaler over 10-20 minutes 90.  Potassium levels should be rechecked in 4 to 6 hours 90.  Oral or rectal sodium polystyrene sulphonate will help with excretion of K.
- Recommended dose is 15-30g orally repeated every 4-6 hours up to 4 times daily as needed based on repeat serum K+ level 90.
- There are no therapies to 'shift' phosphate and the only acute method to reduce phosphate levels in the blood is via renal dialysis. This is rarely indicated for phosphate levels alone but for management of the syndrome of TLS. 4. Hypocalcemia.
- Severe hypocalcemia may cause muscular (cramps, spasms), cardiovascular (ventricular arrhythmias, heart block, hypotension) and neurological (confusion, delirium, hallucinations, seizures) signs. - If hyperphosphatemia is also present, calcium replacement may precipitate calcium phosphate crystals and worsen renal dysfunction.
A renal consult for consideration of dialysis should be initiated prior to any attempts at IV calcium replacement in TLS.
A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010 and updated in 2014 and 2022.
A formal review of the guideline will be conducted in 2025. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.