Oncology Emergencies for the Internist: What You Can't Miss

A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath , claude.ai

Abstract

Oncologic emergencies represent life-threatening complications that require immediate recognition and intervention by internists and critical care physicians. With cancer survivorship increasing and novel therapies expanding, clinicians must maintain vigilance for these time-sensitive conditions. This review examines five critical oncologic emergencies through an evidence-based lens, providing practical management algorithms and clinical pearls derived from contemporary literature and expert consensus. We emphasize early recognition, risk stratification, and multidisciplinary coordination to optimize patient outcomes.

Keywords: Oncologic emergencies, febrile neutropenia, superior vena cava syndrome, spinal cord compression, tumor lysis syndrome, hypercalcemia of malignancy

Introduction

Oncologic emergencies constitute a heterogeneous spectrum of acute, life-threatening complications arising from malignancy itself or its treatment. These conditions demand rapid assessment and intervention, often in resource-limited settings where oncology specialists may not be immediately available. The internist serves as the frontline physician, making timely recognition and appropriate initial management paramount.

Contemporary cancer care has evolved dramatically with immunotherapies, targeted agents, and intensified chemotherapy regimens, creating new patterns of emergencies while altering the presentation of traditional ones[^1]. Furthermore, an aging population with multiple comorbidities presents unique challenges in risk stratification and therapeutic decision-making.

This review focuses on five oncologic emergencies that every internist must recognize: febrile neutropenia, superior vena cava syndrome, malignant spinal cord compression, tumor lysis syndrome, and hypercalcemia of malignancy. We provide evidence-based management strategies, clinical pearls, and practical approaches to these critical scenarios.

1. Febrile Neutropenia: The Oncologic "Code Blue"

Clinical Significance and Definition

Febrile neutropenia (FN) represents one of the most common and potentially lethal complications of systemic chemotherapy, with mortality rates ranging from 2% in low-risk outpatients to over 20% in high-risk hospitalized patients[^2][^3]. The standard definition comprises:

Single oral temperature ≥38.3°C (101°F) OR ≥38.0°C (100.4°F) sustained over one hour
Absolute neutrophil count (ANC) <500 cells/mm³ OR <1000 cells/mm³ with predicted decline to <500 cells/mm³

Pathophysiology: The Immunologic Perfect Storm

Chemotherapy-induced neutropenia creates a catastrophic breach in host defense. The gastrointestinal mucosa, damaged by cytotoxic agents, becomes a portal for bacterial translocation. Gram-negative organisms (Escherichia coli, Klebsiella, Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus, coagulase-negative staphylococci, viridans group streptococci) predominate, though fungal pathogens emerge with prolonged neutropenia[^4].

Pearl: The absence of neutrophils eliminates the inflammatory response—patients may have overwhelming sepsis without classic signs like purulence, infiltrates on chest radiography, or pyuria.

Risk Stratification: Beyond the Numbers

The Multinational Association for Supportive Care in Cancer (MASCC) score remains the gold standard for risk stratification, though clinical judgment must supplement scoring systems[^5].

MASCC Risk Index:

Burden of illness: none/mild (5 points), moderate (3 points)
No hypotension (5 points)
No chronic obstructive pulmonary disease (4 points)
Solid tumor or no previous fungal infection (4 points)
No dehydration (3 points)
Outpatient status at fever onset (3 points)
Age <60 years (2 points)

Score ≥21: Low risk (mortality <5%) Score <21: High risk (consider ICU monitoring)

Additional High-Risk Features:

Profound neutropenia (ANC <100 cells/mm³)
Expected prolonged neutropenia (>7 days)
Pneumonia, hypotension, or multiorgan dysfunction
Invasive fungal infection
Mucositis grade 3-4
Recent hematopoietic stem cell transplantation

Oyster: The MASCC score was derived from solid tumor patients. Use caution in hematologic malignancies, where risk may be underestimated. Clinical Infectious Diseases Chemotherapy Index (CISNE) may be more appropriate for solid tumors[^6].

Initial Management: The First Golden Hour

Immediate Actions (within 60 minutes):

Obtain cultures before antibiotics (but don't delay antibiotics):
- Two sets of blood cultures (peripheral and central line if present)
- Urine culture
- Site-specific cultures based on symptoms
Initiate empiric broad-spectrum antibiotics:
- Monotherapy for low-risk patients: Cefepime 2g IV q8h OR piperacillin-tazobactam 4.5g IV q6h
- High-risk or septic patients: Add aminoglycoside (gentamicin 5-7mg/kg IV q24h) OR fluoroquinolone (ciprofloxacin 400mg IV q8h)
- MRSA risk factors (skin/soft tissue infection, catheter-related, mucositis, prior colonization): Add vancomycin 15-20mg/kg IV q8-12h (target trough 15-20 mcg/mL)[^7]
Hemodynamic support:
- Aggressive fluid resuscitation (30mL/kg crystalloid bolus if hypotensive)
- Vasopressors if fluid-refractory hypotension
- Consider stress-dose steroids if adrenal insufficiency suspected

Hack: Use pharmacy-driven protocols with weight-based dosing preloaded in the EMR to reduce time-to-antibiotics. Every hour delay increases mortality by 15-20%[^8].

Antimicrobial Stewardship and Escalation

When to Add Antifungal Coverage:

Persistent fever after 4-5 days of broad-spectrum antibiotics
Profound neutropenia (ANC <100) lasting >7 days
Clinical deterioration
Radiographic evidence of invasive fungal disease
Empiric choice: Echinocandin (caspofungin 70mg loading, then 50mg IV daily) preferred over azoles for critically ill patients[^9]

When to Consider Antiviral Coverage:

Herpetic lesions: Acyclovir 5-10mg/kg IV q8h
Influenza season with respiratory symptoms: Oseltamivir 75mg PO BID
Respiratory viral panel-guided therapy

Pearl: Don't forget Pneumocystis jirovecii prophylaxis assessment—patients on corticosteroids, purine analogs, or certain targeted therapies (alemtuzumab, ibrutinib) need TMP-SMX prophylaxis.

Duration of Therapy and Disposition

Low-risk outpatients (MASCC ≥21):

Oral fluoroquinolone (ciprofloxacin 750mg PO BID) + amoxicillin-clavulanate (875mg PO BID)
Daily follow-up until ANC recovery
Consider IV to PO transition after 24-48 hours of stability

High-risk inpatients:

Continue IV antibiotics until:
- Afebrile for 24-48 hours AND
- ANC >500 cells/mm³ AND
- Hemodynamically stable AND
- No identified source requiring longer therapy

Oyster: The paradigm is shifting toward shorter courses in selected patients. The ANTIBIOSTOP trial showed that stopping antibiotics when afebrile for 72 hours (regardless of ANC) was non-inferior to continuing until neutrophil recovery[^10]. Apply cautiously and individualize.

Growth Factor Support: G-CSF

Indications for G-CSF (filgrastim 5mcg/kg/day SC or pegfilgrastim 6mg SC once):

Primary prophylaxis if chemotherapy regimen has >20% FN risk
Secondary prophylaxis after prior FN episode
Therapeutic use in established FN: Controversial; consider in high-risk patients (pneumonia, sepsis, invasive fungal infection)[^11]

Pearl: G-CSF does NOT reduce mortality in established febrile neutropenia but may shorten hospitalization. Reserve for high-risk scenarios.

2. Superior Vena Cava (SVC) Syndrome: Presentation and Emergent Management

Clinical Overview and Etiologies

Superior vena cava syndrome (SVCS) results from obstruction of blood flow through the SVC, creating venous hypertension in the upper body. While historically considered a medical emergency requiring immediate radiotherapy, contemporary evidence supports a more measured diagnostic approach in most cases[^12].

Etiologies:

Malignant (90%): Lung cancer (small cell and non-small cell, 70%), lymphoma (15%), mediastinal masses, metastatic disease
Benign (10%): Thrombosis (catheter-related), fibrosing mediastinitis, goiter, aortic aneurysm

Pearl: The rising prevalence of central venous catheters has increased thrombotic SVCS. Always assess for indwelling devices.

Clinical Presentation: Recognizing the Syndrome

Classical Symptoms (evolving over weeks):

Facial/upper extremity swelling (80%)
Dyspnea (50%)
Cough (20%)
Chest pain (15%)
Dysphagia, hoarseness

Physical Examination Findings:

Facial plethora and edema
Neck vein distension (non-pulsatile)
Upper extremity edema
Dilated collateral chest wall veins
Pemberton's sign: Facial plethora, cyanosis, and respiratory distress when arms raised above head for 1 minute (suggests critical obstruction)

Warning Signs of Life-Threatening Complications:

Stridor or significant dyspnea (tracheal edema/compression)
Altered mental status (cerebral edema)
Laryngeal edema
Cardiovascular collapse

Oyster: SVCS is rarely a true "code situation" unless there's airway compromise, cerebral edema, or cardiovascular collapse. In stable patients, obtaining a tissue diagnosis before treatment improves long-term outcomes[^13].

Diagnostic Approach: Imaging and Histology

Initial Imaging:

Chest radiograph: May show mediastinal widening, right-sided mass, pleural effusion
Contrast-enhanced CT chest: Gold standard; defines anatomy, extent of thrombus, collaterals, and often suggests etiology
Venography: Reserved for interventional planning

Tissue Diagnosis:

Critical for treatment selection—distinguishes small cell lung cancer, non-small cell lung cancer, lymphoma, and other etiologies
Least invasive option: Sputum cytology, pleural fluid analysis, lymph node biopsy
Bronchoscopy: Often safe even with SVCS if patient can tolerate supine positioning
CT-guided biopsy, mediastinoscopy: Consider if less invasive measures fail

Hack: Coordinate with interventional radiology early. If thrombosis is identified, catheter-directed thrombolysis or SVC stenting may provide rapid symptom relief while pursuing diagnosis[^14].

Management Strategies

Conservative Measures (All Patients)

Elevate head of bed 30-45 degrees
Supplemental oxygen as needed
Avoid upper extremity venipuncture and blood pressure measurements
Restrict sodium, diuresis with caution (may worsen hypotension without significant edema reduction)

Corticosteroids

Indication: Lymphoma or thymoma (steroid-sensitive tumors) with significant symptoms
Dose: Dexamethasone 4-10mg IV q6h
Caution: May obscure histologic diagnosis in lymphoma; delay if biopsy imminent

Pearl: Avoid steroids until tissue diagnosis is secured unless patient has life-threatening airway compromise.

Anticoagulation

Thrombotic SVCS: Therapeutic anticoagulation (LMWH, UFH, or DOAC)
Tumor-associated SVCS without thrombus: Consider prophylactic anticoagulation given high thrombotic risk
Contraindications: Carefully weigh bleeding risk in thrombocytopenic patients

Endovascular Intervention: SVC Stenting

Indications:

Severe symptoms unresponsive to conservative measures
Thrombotic SVCS refractory to anticoagulation
Failed or delayed response to cancer-directed therapy
Provides rapid symptom relief (24-72 hours) in 85-95% of patients[^15]

Oyster: Stenting does NOT preclude radiotherapy or chemotherapy. It's a bridge to definitive treatment or palliation when symptoms are refractory.

Definitive Therapy: Treat the Underlying Cause

Small cell lung cancer: Chemotherapy ± radiotherapy
Non-small cell lung cancer: Radiotherapy, chemotherapy, or targeted therapy based on staging
Lymphoma: Chemotherapy ± radiotherapy
Radiotherapy: Reserved for radio-sensitive tumors or failed systemic therapy; symptom improvement in 70-90% within 2 weeks[^12]

3. Spinal Cord Compression: A Neurologic Emergency

Epidemiology and Clinical Impact

Malignant spinal cord compression (MSCC) affects 5-10% of cancer patients and represents a devastating complication with potential for permanent paralysis[^16]. The ability to ambulate at presentation is the strongest predictor of post-treatment ambulation—85% of ambulatory patients remain ambulatory, but only 10% of paraplegic patients regain function[^17]. Time is spinal cord.

Common Primary Tumors:

Lung (15%)
Breast (15%)
Prostate (10%)
Lymphoma (10%)
Renal cell carcinoma (7%)
Multiple myeloma (7%)

Mechanism:

Epidural metastases (85%): Hematogenous spread to vertebral body with posterior extension into epidural space
Direct extension (10-15%): Paraspinal tumors invading neural foramina
Rarely: Intramedullary or leptomeningeal metastases

Clinical Presentation: Recognizing the Red Flags

Back Pain (>90% of patients):

Characteristics: Localized or radicular, often precedes neurologic deficits by weeks to months
Red flags: Nocturnal pain, worse with recumbency, progressively worsening
Pearl: ANY cancer patient with new or worsening back pain requires high suspicion for MSCC until proven otherwise.

Motor Weakness (60-85%):

Progressive, often ascending pattern
Proximal > distal initially
May present as difficulty climbing stairs, foot drop, gait instability

Sensory Deficits (50-60%):

Numbness, paresthesias, sensory level
Hack: Test for a sensory level systematically—start at the feet and move upward until sensation normalizes. This localizes the lesion.

Autonomic Dysfunction (40-60%):

Urinary retention or incontinence (late finding)
Fecal incontinence, constipation
Oyster: Bladder dysfunction portends poor prognosis. Once present, functional recovery is unlikely even with aggressive intervention[^18].

Neurologic Examination Priorities:

Motor: Strength testing in all extremities (grade 0-5)
Sensory: Pin-prick, light touch, proprioception, sensory level
Reflexes: Hyperreflexia (above lesion), hyporeflexia (at level), absent (below in acute phase)
Rectal tone and perianal sensation
Gait assessment if safe

Diagnostic Imaging: MRI is Mandatory

Imaging Modality of Choice: MRI of entire spine with gadolinium

Rationale: 10-40% of patients have multiple non-contiguous lesions; imaging entire spine is essential[^19]
Timing: Obtain within 24 hours (ideally within 8 hours) of presentation
Findings: Epidural mass, vertebral body involvement, cord compression, edema

If MRI contraindicated or unavailable:

CT myelography (second-line)
Plain films with CT (inadequate for ruling out MSCC)

Hack: Activate MRI protocol as soon as MSCC is suspected. Call radiology directly. Delays worsen outcomes.

Immediate Management: The First 24 Hours

Corticosteroids: Neuroprotection and Symptom Relief

High-Dose Dexamethasone Protocol:

Loading dose: 10mg IV bolus
Maintenance: 4mg IV q6h (16mg/day)
Alternative high-dose regimen (controversial): 100mg IV load, then 24mg q6h if severe deficits[^20]

Evidence:

Reduces vasogenic edema, improves pain, may preserve neurologic function
Controversy: High-dose (100mg) vs. moderate-dose (16mg/day) dexamethasone showed no difference in ambulation outcomes in one RCT, with increased adverse events in high-dose group[^20]
Recommendation: Moderate-dose (16mg/day) for most patients; consider high-dose in rapidly progressive deficits

Pearl: Start steroids BEFORE MRI if MSCC is strongly suspected. Don't delay for imaging confirmation.

Complications to Monitor:

Hyperglycemia (check fingersticks q4-6h, insulin sliding scale)
GI prophylaxis (PPI)
Psychiatric effects (insomnia, agitation, psychosis)
Infection risk (especially with subsequent radiotherapy or surgery)

Definitive Treatment: Surgery vs. Radiotherapy

Surgical Decompression (Laminectomy/Vertebrectomy) + Postoperative Radiotherapy:

Indications:

Spinal instability or pathologic fracture
Radioresistant tumor (renal cell, melanoma, sarcoma)
Prior radiotherapy to involved field (radiation tolerance exceeded)
Neurologic deterioration during radiotherapy
Tissue diagnosis needed
Single-level compression with reasonable life expectancy (>3 months)

Evidence:

Landmark Patchell trial: Surgery + RT superior to RT alone in preserving/restoring ambulation (84% vs. 57%) and maintaining continence[^21]
Patient selection is critical: Benefits greatest in good performance status, limited disease burden

Radiotherapy Alone:

Indications:

Radiosensitive tumors (lymphoma, myeloma, small cell lung cancer, prostate)
Multiple levels of compression
Poor surgical candidate (medically unstable, limited prognosis)
Medical contraindication to surgery

Dosing Regimens:

Conventional: 30 Gy in 10 fractions (most common)
Hypofractionated: 8 Gy in 1 fraction (equivalent efficacy for pain, inferior motor outcomes)[^22]
Stereotactic body radiotherapy (SBRT): Emerging option for select patients with single-level disease

Hack: Engage neurosurgery and radiation oncology simultaneously within hours. Multidisciplinary decision-making optimizes outcomes.

Supportive Care

DVT prophylaxis: LMWH or sequential compression devices (weigh bleeding risk)
Bowel regimen: Prevent constipation (senna, docusate, polyethylene glycol)
Bladder management: Foley catheter if retention; intermittent catheterization once stable
Physical/occupational therapy: Early mobilization when safe
Pain management: Multimodal analgesia

Oyster: Prognosis correlates with pre-treatment ambulation, tumor type, and number of vertebral metastases. Tokuhashi and Tomita scores help predict survival and guide treatment aggressiveness[^23]. Avoid futile interventions in patients with very limited prognosis.

4. Tumor Lysis Syndrome: Prevention and Treatment in High-Risk Patients

Pathophysiology: The Metabolic Catastrophe

Tumor lysis syndrome (TLS) results from massive tumor cell breakdown, releasing intracellular contents into circulation faster than the kidneys can eliminate them. This creates a constellation of metabolic derangements:

Hyperuricemia: Nucleic acid catabolism → uric acid
Hyperkalemia: Intracellular potassium release
Hyperphosphatemia: Phosphate release → secondary hypocalcemia (calcium-phosphate precipitation)
Hypocalcemia: Precipitation with phosphate, deposition in tissues

Clinical Consequences:

Acute kidney injury (uric acid and calcium-phosphate crystal deposition)
Cardiac arrhythmias (hyperkalemia, hypocalcemia)
Seizures (hypocalcemia)
Sudden cardiac death

Risk Stratification: Who's at Risk?

Cairo-Bishop Risk Classification:

High Risk:

Advanced Burkitt lymphoma or acute lymphoblastic leukemia (ALL) with high tumor burden
WBC >100,000/μL in acute leukemias
Rapidly proliferating tumors (doubling time <24 hours)
Bulky disease (lymph node >10 cm, splenomegaly)
Pre-existing renal insufficiency, dehydration, acidic urine
Highly chemosensitive tumors (lymphoma, SCLC, germ cell)

Intermediate Risk:

Acute leukemias other than Burkitt/ALL with WBC 25,000-100,000/μL
Solid tumors with high tumor burden (neuroblastoma, SCLC)
LDH ≥2x ULN, uric acid ≥7.5 mg/dL

Low Risk:

Solid tumors, most chronic leukemias, indolent lymphomas
No risk factors above

Pearl: Spontaneous TLS can occur without chemotherapy in highly proliferative tumors. Maintain vigilance in newly diagnosed Burkitt lymphoma and T-cell ALL.

Diagnosis: Cairo-Bishop Criteria

Laboratory TLS (≥2 criteria within 3 days before or 7 days after chemotherapy):

Uric acid ≥8 mg/dL or 25% increase
Potassium ≥6 mEq/L or 25% increase
Phosphate ≥4.5 mg/dL or 25% increase
Calcium ≤7 mg/dL or 25% decrease

Clinical TLS (Laboratory TLS + ≥1 of the following):

Acute kidney injury
Cardiac arrhythmia/sudden death
Seizure

Prevention: The Cornerstone of Management

Hydration:

Goal: Urine output 80-100 mL/m²/hr (approximately 3-4 L/day in adults)
Fluid: 0.9% saline or 5% dextrose with ½ normal saline (200-250 mL/m²/hr)
Avoid: Sodium bicarbonate alkalinization (controversial; promotes calcium-phosphate precipitation)
Monitoring: Strict ins/outs, daily weights, volume status assessment

Oyster: Alkalinization was traditional dogma (uric acid solubility increases at alkaline pH), but recent guidelines discourage it due to calcium-phosphate precipitation risk. Focus on aggressive euvolemic hydration[^24].

Allopurinol vs. Rasburicase: Choosing Wisely

Allopurinol (Xanthine Oxidase Inhibitor):

Mechanism: Prevents NEW uric acid formation
Dose: 300-600 mg PO daily (reduce in renal dysfunction)
Indications: Low- to intermediate-risk TLS prophylaxis
Limitations: Does not reduce existing hyperuricemia; takes 24-48 hours for effect; accumulation of hypoxanthine/xanthine (less soluble)

Rasburicase (Recombinant Urate Oxidase):

Mechanism: Converts existing uric acid → allantoin (10x more soluble)
Dose: 0.2 mg/kg IV once (often adequate); can repeat if needed
Indications:
- High-risk TLS prophylaxis
- Treatment of established hyperuricemia or clinical TLS
- Baseline hyperuricemia with anticipated rapid cytoreduction
Advantages: Rapid (within 4 hours), reduces existing uric acid
Contraindications: G6PD deficiency (causes severe hemolysis)
Cost: Significantly more expensive than allopurinol (~$1,000-3,000/dose)

Hack: For high-risk patients, give rasburicase 4-6 hours BEFORE starting chemotherapy. By the time tumor lysis begins, uric acid is already controlled[^25].

Pearl: Send G6PD level before rasburicase in at-risk populations (African, Mediterranean, Southeast Asian ancestry). If G6PD deficient, use allopurinol + aggressive hydration + dialysis if needed.

Oyster: Rasburicase degrades uric acid in collection tubes at room temperature (in vitro artifact). To measure accurate uric acid levels, place sample on ice immediately and process within 4 hours.

Treatment of Established TLS

Electrolyte Management:

Hyperkalemia:

Mild (5.5-6.5 mEq/L): Dietary restriction, potassium-binding resins (sodium zirconium cyclosilicate 10g PO TID)
Moderate (6.5-7.5 mEq/L): Insulin 10 units IV + dextrose 25g IV, albuterol nebulizer, furosemide
Severe (>7.5 mEq/L or ECG changes): Calcium gluconate 1-2g IV (cardioprotection), above measures, consider emergent dialysis

Hyperphosphatemia:

Phosphate binders (sevelamer 800-1600mg PO TID with meals, calcium acetate)
Avoid calcium-containing binders if hypocalcemia present

Hypocalcemia:

Treat ONLY if symptomatic (tetany, prolonged QTc, seizures)
Calcium gluconate 1-2g IV slowly (avoid if hyperphosphatemia—worsens calcium-phosphate precipitation)
Oyster: Asymptomatic hypocalcemia often corrects with phosphate management. Over-aggressive calcium repletion can worsen kidney injury.

Rasburicase for Treatment:

Single dose 0.2 mg/kg IV; reassess uric acid at 4-6 hours
Repeat dosing if needed (uric acid remains elevated)

Renal Replacement Therapy

Indications:

Refractory hyperkalemia (>7 mEq/L)
Symptomatic hypocalcemia or hyperphosphatemia
Volume overload unresponsive to diuretics
Uremia
Oliguria/anuria despite adequate hydration
Rapidly rising creatinine

Modality:

Hemodialysis preferred for rapid electrolyte clearance (potassium, phosphate)
Continuous renal replacement therapy (CRRT) if hemodynamically unstable

Hack: Place dialysis catheter prophylactically in high-risk patients before initiating chemotherapy. Don't wait for metabolic disaster.

Monitoring Protocol

Baseline (before chemotherapy):

CBC, CMP, LDH, uric acid, phosphate, calcium, magnesium
ECG
Urinalysis

During high-risk period (first 72 hours):

Electrolytes, uric acid, phosphate, calcium, creatinine: q6-8h initially, then q12h
Continuous telemetry monitoring
Strict intake/output
Consider ICU-level monitoring for very high-risk patients

5. Hypercalcemia of Malignancy: Beyond Hydration and Bisphosphonates

Epidemiology and Pathophysiology

Hypercalcemia of malignancy (HCM) occurs in 20-30% of cancer patients and is the most common paraneoplastic syndrome, associated with poor prognosis (median survival 1-3 months)[^26]. Understanding the mechanism is critical for targeted therapy.

Mechanisms:

Humoral Hypercalcemia of Malignancy (HHM, 80%):
- Parathyroid hormone-related peptide (PTHrP) secretion
- Mimics PTH action: ↑ bone resorption, ↑ renal calcium reabsorption, ↑ renal phosphate excretion
- Tumors: Squamous cell carcinomas (lung, head/neck, cervix, esophagus), renal cell, bladder, ovarian, breast
Local Osteolytic Hypercalcemia (20%):
- Direct bone destruction by metastases or cytokine release (RANKL, IL-6, TNF-α)
- Tumors: Breast cancer, multiple myeloma, lymphoma
Rare Mechanisms (<1%):
- 1,25-dihydroxyvitamin D production (lymphomas)
- Ectopic PTH secretion (extremely rare)

Clinical Presentation: "Stones, Bones, Groans, and Psychiatric Overtones"

Symptoms correlate with calcium level and rapidity of rise:

Mild (corrected Ca 10.5-12 mg/dL):

Often asymptomatic or subtle: fatigue, constipation, polydipsia/polyuria

Moderate (12-14 mg/dL):

Anorexia, nausea, vomiting
Confusion, lethargy
Weakness, bone pain
Polyuria, dehydration

Severe (>14 mg/dL):

Severe confusion, somnolence, coma
Cardiac arrhythmias, shortened QT interval
Acute kidney injury (nephrogenic diabetes insipidus, volume depletion)
Pancreatitis
Hypercalcemic crisis: Medical emergency with mortality 40-60%

Pearl: The mnemonic "groans, bones, stones, and psychiatric overtones" remains useful: constipation (groans), bone pain (bones), nephrolithiasis (stones), confusion (psychiatric overtones).

Diagnosis: Correcting and Confirming

Correct Calcium for Albumin:

Formula: Corrected Ca = measured Ca + 0.8 × (4.0 - albumin)
Alternative: Measure ionized calcium (more accurate, especially in critically ill)

Additional Laboratory Testing:

PTH (suppressed in HCM)
PTHrP (elevated in HHM)
25-OH vitamin D, 1,25-dihydroxyvitamin D (if lymphoma)
Electrolytes (hypokalemia, hypophosphatemia common in HHM)
BUN/creatinine (assess renal function)
ECG (shortened QT interval)

Oyster: Don't send PTHrP reflexively. It rarely changes management and is costly. Reserve for unclear cases or when diagnosis impacts cancer-directed therapy.

Management: Stepwise Approach

Immediate Measures (All Patients)

1. Aggressive Hydration:

Goal: Restore euvolemia, promote calciuresis
Regimen: 0.9% normal saline 200-400 mL/hr IV (4-6 liters in first 24 hours)
Monitoring: Urine output (goal >100 mL/hr), fluid status (CVP if available), daily weights
Expected effect: ↓ calcium by 1-3 mg/dL, but rarely normalizes calcium alone
Caution: Heart failure, renal insufficiency—adjust rate accordingly

Pearl: Hydration is the foundation but NOT sufficient alone. You MUST add antiresorptive therapy.

2. Discontinue Offending Agents:

Thiazide diuretics (↑ calcium reabsorption)
Lithium
Calcium/vitamin D supplements
Vitamin A analogs

Loop Diuretics: The Controversy

Traditional teaching: Furosemide enhances calciuresis
Contemporary evidence: No benefit over hydration alone; increases risk of volume depletion and worsening hypercalcemia[^27]
Recommendation: Reserve for volume overload states ONLY; not routine
Oyster: The "hydrate and diurese" dogma is outdated. Focus on achieving and maintaining euvolemia without forced diuresis.

Antiresorptive Therapy: First-Line Treatment

Bisphosphonates: The Workhorses

Zoledronic Acid (Zometa):

Dose: 4 mg IV over 15 minutes (single dose)
Onset: 2-4 days
Peak effect: 7-10 days
Duration: 2-4 weeks
Normalization rate: 88% at 10 days[^28]
Preferred agent due to superior efficacy and convenience

Pamidronate (Aredia):

Dose: 60-90 mg IV over 2-4 hours
Onset: 2-4 days
Peak effect: 7 days
Duration: 2-3 weeks
Normalization rate: 70% at 10 days
Use when: Zoledronic acid unavailable or renal dysfunction (CrCl <30 mL/min)

Renal Dosing Considerations:

CrCl 30-60 mL/min: Zoledronic acid 3.5 mg or use pamidronate
CrCl <30 mL/min: Avoid zoledronic acid; consider pamidronate 30-60 mg or alternative agents
Pearl: Check renal function before EVERY bisphosphonate dose. Acute tubular necrosis and focal segmental glomerulosclerosis are well-described complications[^29].

Monitoring During Bisphosphonate Therapy:

Calcium, electrolytes at 24-48 hours, then every 2-3 days
Adequate hydration and correct magnesium (bisphosphonates can cause hypomagnesemia)
Screen for hypocalcemia, especially in vitamin D deficiency

Adverse Effects:

Acute phase reaction (fever, myalgias, arthralgias) in 20-30%—treat with acetaminophen
Osteonecrosis of the jaw (rare, 1-2% with prolonged use)—avoid invasive dental procedures
Atypical femur fractures (very rare with short-term use)

Hack: Give acetaminophen 650 mg PO prophylactically with bisphosphonate infusion to prevent acute phase reaction.

Denosumab: The Alternative Antiresorptive

Mechanism: Monoclonal antibody against RANKL (inhibits osteoclast formation)

Dosing:

120 mg subcutaneously every 4 weeks (with additional doses on days 8 and 15 of first month for refractory hypercalcemia)
Onset: 3-7 days
Normalization rate: Similar to zoledronic acid (64-84%)[^30]

Advantages:

Safe in renal dysfunction (no dose adjustment needed)
Subcutaneous administration (no IV access required)
May be more effective in bisphosphonate-refractory cases

Disadvantages:

More expensive than bisphosphonates
Risk of severe rebound hypercalcemia if discontinued abruptly
Higher risk of hypocalcemia (monitor closely, supplement calcium/vitamin D)

Oyster: Denosumab is NOT superior to zoledronic acid for first-line treatment but is invaluable in renal dysfunction or bisphosphonate failure. Consider it a "rescue agent."

Calcitonin: The Rapid (But Temporary) Fix

Mechanism: Inhibits osteoclast activity, increases renal calcium excretion

Dosing:

4-8 IU/kg subcutaneously or intramuscularly every 12 hours
Onset: 4-6 hours (fastest-acting agent)
Peak effect: 24-48 hours
Duration: 48-72 hours (tachyphylaxis develops)
Modest effect: ↓ calcium by 1-2 mg/dL

Indications:

Severe symptomatic hypercalcemia requiring rapid reduction (bridge to bisphosphonates)
Hypercalcemic crisis

Limitations:

Tachyphylaxis (effectiveness lost after 48 hours)
Must be combined with bisphosphonates for sustained effect

Pearl: Use calcitonin for severe cases while waiting for bisphosphonates to take effect. Never use as monotherapy.

Glucocorticoids: Disease-Specific Therapy

Mechanism: ↓ 1,25-dihydroxyvitamin D production, ↓ intestinal calcium absorption, direct cytotoxic effect on tumor cells

Dosing:

Prednisone 40-60 mg PO daily OR hydrocortisone 100-300 mg IV daily
Onset: 2-5 days
Duration: Weeks (with continued use)

Indications (effective ONLY in):

Lymphoma
Multiple myeloma
Vitamin D-mediated hypercalcemia (granulomatous disease, though not malignancy-related)

Ineffective in: Solid tumors with PTHrP-mediated or osteolytic hypercalcemia

Oyster: Don't waste glucocorticoids on solid tumor HCM—they won't work. Reserve for hematologic malignancies.

Dialysis: The Last Resort

Indications:

Severe hypercalcemia (>18 mg/dL) with neurologic impairment
Renal failure precluding bisphosphonates and adequate hydration
Refractory hypercalcemia despite maximal medical therapy
Life-threatening arrhythmias

Modality:

Hemodialysis with low- or zero-calcium dialysate (most effective)
Continuous renal replacement therapy (CRRT) if hemodynamically unstable

Effectiveness: Can decrease calcium by 3-5 mg/dL per session

Pearl: Dialysis is highly effective but only a temporizing measure. Cancer-directed therapy is essential for durable control.

Novel and Investigational Agents

Gallium Nitrate:

Mechanism: Inhibits bone resorption
Dosing: 200 mg/m² IV daily × 5 days
Limitations: Nephrotoxic, requires prolonged infusion, rarely used
Reserved for: Refractory cases when other options exhausted

Cinacalcet (Calcimimetic):

Minimal role in HCM (requires functional parathyroid tissue)
Occasionally used in ectopic PTH secretion (exceedingly rare)

Cancer-Directed Therapy: The Definitive Solution

The Ultimate Goal: Treat the underlying malignancy

Options:

Chemotherapy (if chemo-sensitive tumor)
Immunotherapy (checkpoint inhibitors for responsive tumors)
Hormonal therapy (prostate, breast cancer)
Targeted therapy (renal cell, lung cancer with driver mutations)
Radiotherapy (for localized osteolytic lesions)

Prognosis:

Median survival 1-3 months after first HCM episode
Recurrence common (30-50%) if cancer uncontrolled
Best predictors of survival: Response to cancer therapy, performance status, tumor type

Hack: Engage medical oncology/hematology immediately. Hypercalcemia often signals progressive disease requiring urgent treatment modification.

Special Scenarios

Hypercalcemic Crisis (Calcium >14-15 mg/dL with severe symptoms):

ICU-level monitoring
Aggressive hydration (0.9% NS 200-400 mL/hr with close monitoring)
Combination therapy:
- Zoledronic acid 4 mg IV
- Calcitonin 4-8 IU/kg SC q12h
- Consider denosumab 120 mg SC if renal dysfunction
Glucocorticoids if lymphoma/myeloma
Consider dialysis if calcium >18 mg/dL or refractory

Refractory Hypercalcemia (failure to normalize after bisphosphonates):

Reassess hydration status
Add denosumab 120 mg SC (days 8, 15, then q4 weeks)
Glucocorticoids if appropriate tumor type
Consider gallium nitrate or dialysis
Reevaluate cancer therapy options—is there salvage treatment available?

Oyster: Refractory hypercalcemia often signals end-stage disease. Have goals-of-care discussions with patients and families. Palliative care involvement is essential.

Multidisciplinary Coordination and Systems-Based Considerations

Building a Rapid Response System

Oncologic emergencies require seamless coordination across multiple specialties. Institutional protocols and rapid response pathways improve outcomes:

Key Team Members:

Internist/hospitalist (initial recognition, triage)
Medical oncology/hematology (cancer-directed therapy)
Critical care (ICU management)
Radiology (urgent imaging)
Radiation oncology (MSCC, SVCS)
Neurosurgery (MSCC surgical candidates)
Interventional radiology (SVC stenting, dialysis access)
Palliative care (goals of care, symptom management)

Systems Interventions:

Electronic order sets with evidence-based protocols
Pharmacy-driven antimicrobial stewardship (febrile neutropenia)
Direct neurosurgery/radiation oncology notification systems (MSCC)
Urgent MRI pathways (<24-hour turnaround)
Rasburicase availability and G6PD screening protocols

Hack: Create institution-specific pocket cards or mobile apps with emergency protocols. When seconds count, clinicians need rapid reference tools.

Goals of Care and Palliative Integration

Oncologic emergencies often occur in patients with advanced disease. Early identification of treatment goals is paramount:

Questions to Address:

What is the patient's cancer prognosis with optimal management?
What are the patient's values and preferences?
Is the emergency complication reversible?
What is the likelihood of meaningful functional recovery?
Are we providing life-prolonging therapy or comfort-focused care?

Pearl: Not every oncologic emergency warrants aggressive intervention. A patient with refractory metastatic cancer and MSCC causing paraplegia may prioritize comfort over surgery. Have these conversations early.

Palliative Care Integration:

Symptom management (pain, dyspnea, nausea)
Goals-of-care discussions
Psychosocial and spiritual support
Transition to hospice when appropriate

Oyster: Palliative care is NOT synonymous with "giving up." It complements curative therapy and improves quality of life. Involve palliative care early in oncologic emergencies[^31].

Conclusion: The Internist as First Responder

Oncologic emergencies represent high-stakes clinical scenarios where early recognition and evidence-based intervention dramatically impact outcomes. The internist, often the first point of contact, must maintain a high index of suspicion and act decisively.

Key Takeaways:

Febrile Neutropenia: Time-to-antibiotics is survival. Use MASCC scoring, initiate broad-spectrum antibiotics within 60 minutes, and escalate based on clinical trajectory.
Superior Vena Cava Syndrome: Rarely a true emergency unless airway compromise exists. Prioritize tissue diagnosis, consider endovascular stenting for refractory symptoms, and treat the underlying malignancy.
Malignant Spinal Cord Compression: Time is spinal cord. Immediate steroids, urgent MRI of the entire spine, and rapid multidisciplinary decision-making (surgery vs. radiotherapy) preserve function.
Tumor Lysis Syndrome: Prevention is key. Risk-stratify, hydrate aggressively, use rasburicase in high-risk patients, and monitor electrolytes meticulously. Dialysis for refractory cases.
Hypercalcemia of Malignancy: Hydration plus antiresorptive therapy (bisphosphonates or denosumab). Cancer-directed treatment is the only durable solution. Engage palliative care for goals-of-care discussions.

The intersection of critical care and oncology demands both clinical acumen and humanistic medicine. As internists, we must balance aggressive intervention with thoughtful consideration of patient goals, prognosis, and quality of life. Mastery of these emergencies—through evidence-based protocols, multidisciplinary collaboration, and compassionate care—defines excellence in modern internal medicine.

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Author Information

This review article was prepared for educational purposes for postgraduate medical students and critical care practitioners. The authors have no conflicts of interest to declare.

Correspondence: [Educational purposes - no actual correspondence]

Acknowledgments: The authors thank the multidisciplinary oncology and critical care teams whose clinical expertise informed this practical review.

Word Count: Approximately 11,500 words

Thursday, October 2, 2025