Oncological Emergencies Dr. Gary Harding md, frcpc

Oncological Emergencies

• Dr. Gary Harding MD, FRCPC

• Medical Oncology Fellow CancerCare Manitoba

CASE 1…

Mr. SV

• ID: 65 year old male with PMHx of CAD and emphysema

• EC: present to clinic with one week history of increasing SOB

• HPI: 3 month history of weight loss, decreased appetite, a change in his chronic cough, and intermittent hemoptysis

On Physical Examination

• Inspection:

Respiratory Examination

• Stridor

• Dullness to percussion on right lower lung fields

• Increased tactile fremitus to right lower lung fields

• Decreased A/E to right lower lung fields

Chest X-Ray…

Thoracentesis

• Exudate

• Gram stain

• Negative

• AFB stain

• Negative

• Cytology

• non-small cell lung cancer
• Large cell type

Superior Vena Cava Syndrome

Definition

• Obstruction of blood flow in the superior vena cava results in signs and symptoms of SVC syndrome

Etiology

• Caused by either invasion or external compression of the SVC by contiguous pathologic process

• Right lung pathology, lymph nodes, other mediastinal structures, or thrombosis

Etiology

• Before antibiotics the most common causes were from complications of untreated infection

• Syphilitic thoracic aneurysms
• fibrosing mediastinitis

• Malignancy is presently the most common cause

Symptoms and Signs

• As the obstruction develops venous collaterals are formed

• Symptom onset depends on speed of SVC obstruction onset

• Malignant disease can arise in weeks to months

• Not enough time to develop collaterals

• Fibrosing mediastinitis can take years to have symptoms

Symptoms and Signs

• Central venous pressures remain high even in collaterals

• High pressures cause the characteristic clinical picture

• Shortness of breath is the most common symptom1

Signs and Symptoms

• Facial swelling or head fullness

• exacerbated by bending forward or lying down

• Cough

• Arm edema

• Cyanosis

Physical Findings

• Venous distension

• neck
• chest wall

• Pemberton’s Sign

• Facial Edema

Etiology: Malignancy

• Lung cancer is the most common2

• Lymphoma is second most common

• together represent 94% of cases

NSCLC

• 2-4% of bronchogenic cancer patients develop SVC syndrome3

• extrinsic compression or direct invasion

• primary tumor or by enlarging mediastinal nodes

Small Cell Lung Cancer

• Greatest risk

• 20% will develop SVC obstruction3

• more common because SCLC tends to occur centrally in contrast to other types

Lymphoma

• 2-4% of patients

• predominantly non-Hodgkin’s lymphoma4

• Hodgkin’s rarely causes SVC syndrome

Lymphoma

• Extrinsic compression caused by enlarging lymph nodes

• subtypes of large B cell can be intravascular and cause occlusion (angiotropic)

• diffuse large cell and lymphoblastic are most commonly associated with SVC syndrome

Other cancers

• Thymoma

• primary mediastinal germ cell neoplasm

• solid tumors with mediastinal nodal metastases

• breast cancer most common type

Other causes

• Post radiation local vascular fibrosis can also be considered in oncology patients

• Thoracic radiation treatment may predate syndrome by many years

Other causes

• Thrombosis

• Indwelling central venous catheters

• Subcutaneous tunneled catheters have fewer thrombotic and infectious complications

• Can also cause pulmonary embolism5

Diagnosis

• Timely identification of the cause is essential

• Radiographic studies are useful

• Up to 60% of patients with SVC syndrome related to neoplasm do not have a known diagnosis of cancer6

• Need a tissue biopsy for histologic studies

Radiographic Studies

• Most patients have an abnormal chest x-ray at presentation

• Most common findings are

• Mediastinal widening
• Pleural effusion

CT Chest

• Preferred choice

• IV contrast

• defines the level of obstruction
• Maps out collateral pathways
• Can identify underlying cause of obstruction

Venography

• Bilateral upper arm venograpy

• superior to CT to define site of obstruction
• Does not define cause unless thrombosis is solely responsible

Helical CT

• With bilateral upper arm IV contrast injection

• Best visualization of level of obstruction and cause

MRI

• Can be useful in patients with IV contrast allergies

Histologic Diagnosis

• Essential

• Guides treatment

• Aids in defining prognosis

Histologic Diagnosis

• Sputum cytology, pleural fluid cytology, biopsy of enlarged peripheral nodes

• Bone marrow biopsy for NHL

• Bronchoscopy, mediastinoscopy, or thoracotomy are more invasive but sometimes necessary

Treatment of Oncologic Causes

Treatment

• Aimed at underlying cause

• Evolution of thought has occurred in recent years

Historically SVC syndrome was considered a potentially life-threatening emergency

• Historically SVC syndrome was considered a potentially life-threatening emergency

• Standard of care was immediate radiotherapy

• Zap now
• Ask questions later

• The emergent approach is not appropriate for most patients

Newer strategies

Emergent to Urgent

• Symptomatic obstruction is usually a prolonged process

• Most patients are not in immediate danger at presentation

• Most have time for a full diagnostic work up

Emergent to Urgent

• Prebiopsy radiation can obscure the diagnosis

• Current strategies aim at accurate diagnosis of underlying etiology before therapy

Exception to new rule

• Stridor

• Central airway obstruction or laryngeal edema

• True medical emergency

• Immediate action needed

• Possible intubation and ICU admission
• Immediate therapy to target obstruction needed

Prognosis…

• Linked to tumor histology and stage at presentation

Treatment Sensitive Tumors

• NHLs, germ cells, and limited-stage small cell lung cancers usually respond to chemotherapy and or radiation

• Can achieve long term remission with tumor specific directed therapy

• Symptomatic improvement usually takes 1-2 weeks after start of therapy

Note: Corticosteroids

• Controversial issue with regards to treatment benefit at presentation

Non-small cell lung cancer

• SVC obstruction is a strong predictor of poor prognosis

• Median survival around 5 months7

• Choice of therapy considers likelihood of response to each modality

Non-small cell lung cancer

• Goal usually directed to palliation rather than long term remission

• Palliative radiation and chemotherapy can be used

Intraluminal Stents

• Endovascular placement under fluoroscopy

• Patients who have recurrent disease in previously irradiated fields

• Tumors refractory chemotherapy

• Patient too ill to tolerate radiation or chemotherapy

Intraluminal Stents

• Some data suggests benefit from immediate stent placement in NSCLC at presentation8

• Tends to provide more rapid relief of symptoms

• Issue of anticoagulation after is not resolved

CASE 2…

Mr. EC

• ID: 56 year old man with history of HTN and osteoarthrtis

• EC: presents to family doctor with one month history of back pain that is not responding to Tylenol

• Pain beginning to wake him at night
• More pain with recumbancy
• Some shooting pains down right leg

• ROS: negative

On examination

• vitals stable, no fever

• CVS, Respiratory, GI, GU exams reported as normal

• Back exam

• Inspection: normal
• Palpation: some pain in L1
• ROM: normal
• Some pain in right leg with straight leg raising

Investigation in Clinic

• Lumbar Spine X-ray

• Some age related degeneration

Diagnosis

• Sciatica vs. Back strain

• Treatment:

• NSAIDS
• Few days of bed rest

The story continues…

• Mr. EC’s pain does not resolve

• More trials of various forms of pain control fail

• One month later Mr. EC awakens in the morning and has difficulty supporting his weight

• Subjective leg muscle weakness

• Goes to HSC Emergency room

In ER

• Patient has objective leg weakness on physical exam

• A very keen medical student does a rectal exam and discovers a large nodular prostate

• PSA: 45.0

• MRI Spine…..

Spinal Cord Compression

Malignant Epidural Spinal Cord Compression (ESCC)

• Neoplastic invasion of the space between vertebrae and spinal cord (epidural invasion)

• Usually from bone metastases

• Compresses thecal sac of spinal cord

• Frequent complication of malignancy

• Can cause pain

• Can cause irreversible loss of neurologic function

Definition

• Any radiological indentation of the thecal sac

• Tip of the spinal cord lies at the L1 vertebral level

• Lumbosacral nerve roots form the cauda equina

Epidemiology

• Many cases of unrecognized ESCC

• Difficult to define incidence

• Autopsy review studies suggest around 5% of cancer patients die with ESCC9

Causes

• Metastatic tumor from any primary site

• Tumors with predilection to metastasize to spinal column

• Prostate, breast, and lung carcinoma

• 15-20% of cases

• Renal cell, non-Hodgkin’s lymphoma, or myeloma

• 5-10% of cases

Vertebral metastases are more common than ESCC

• Vertebral metastases are more common than ESCC

• Prostate cancer: 90%

• Breast Cancer: 74%

• Lung Cancer: 45%

• Lymphoma: 29%

• Renal cell: 29%

• GI: 25%

• ESCC can be initial presentation of a malignancy

• Around 20% of cases
• In many cases diagnosis is made by biopsy of the spinal lesion

Spinal Location10

• Thoracic spine: 60%

• Lumbosacral spine: 30%

• Cervical spine: 10%

• Specific tumor predilection is difficult to define

Clinical Features

Important to recognize

• Important to recognize

• Early recognition leads to better outcomes

• Efficacy of treatment depends most on patient’s neurological function at presentation

• Median time from symptoms to diagnosis is around 2 months11

• More than half of patients who present to hospital are non-ambulatory

RED FLAGS…..

First Red Flag: Pain

• Usually first symptom12

• 80-90% of the time

• Usually precedes other neurologic symptoms by seven weeks

• Increases in intensity

• Severe local back pain

• Aggravated by recumbency

• Distension of venous plexus

• May become radicular

Second Red Flag: Motor

• Weakness: 60-85%13

• At or above conus medularis

• Extensors of the upper extremities

• Above the thoracic spine

• Weakness from corticospinal dysfunction
• Affects flexors in the lower extremities

• Patients may be hyperreflexic below the lesion and have extensor plantars

Weakness tends to be symmetrical

• Weakness tends to be symmetrical

• Progressive weakness is followed by lost of gait function then paralysis

• The severity of weakness is greatest with thoracic metastases

Third Red Flag: Sensory

• Less common than motor findings

• Still present in majority of cases

• Ascending numbness and parathesias

Fourth Red Flag: Bladder and Bowel Function

• Loss is late finding

• Autonomic neuropathy presents usually as urinary retension

• Rarely sole finding

Radiologic Investigation

Diagnosis depends on ability to demonstrate a mass compressing the thecal sac

• Diagnosis depends on ability to demonstrate a mass compressing the thecal sac

• Plain radiographs are not enough

• Historically this involved invasive procedures

• Advent of MRI has allowed non-invasive diagnosis

• Clinical examination is not reliable in determining level of lesion

Entire imaging of spine is ideal

• Entire imaging of spine is ideal

• Focused CT imaging can miss clinically unapparent lesions

• Myelography and MRI are better than plain X-Rays, bone scans and CT for diagnosis

Plain Spine Radiographs

• Easiest and cheapest

• Need large bony destruction or vertebral collapse to be diagnostic

• High false negative rate

• Not recommended to confirm diagnosis

MRI vs. CT Myelography

Both image thecal sac and display indentation and encircling

• Both image thecal sac and display indentation and encircling

• CT myelography involves a lumbar puncture

• Contraindicated in brain metastases, thrombocytopenia, or coagulopathy
• Can diagnose leptomeningeal metastases
• Available in Winnipeg in middle of the night

MRI

• Images whole spine

• High detail

• Spares lumbar puncture

• Patients in pain must lie still

Roughly equivalent in terms of sensitivity and specificity

• Roughly equivalent in terms of sensitivity and specificity

• Presently no large comparative studies b/c MRI in the US has become so readily available

• MRI standard of care in centers that have access

Bone Scan

• More sensitive than plain radiograph

• Visualizes entire skeleton

• Can miss neoplasms that do not have increased blood flow

CT Scan alone

• Does not visualize spinal cord and epidural space clearly

Intramedullary Metastases

• Less common

• Often present with hemicord symptoms

• Unilateral weakness below lesion
• Contralateral diminution of pain and temperature sensation
• Can progress to bilateral dysfunction

Radiation Myelopathy

• Can mimic ESCC

• MR imaging can make distinction

Treatment

Treatment delays…….

• 2 month median delay in treatment from onset of back pain11

• 14 day delay in treatment from onset of neurological symptoms11

Why the delay?

• Patient factors

• General practitioner factors

• Hospital factors

• EDUCATION

Treatment Objectives

• Pain control

• Avoidance of complications

• Preserve or improve neurological function

Pain management

• Corticosteroids

• Decrease edema

• Opiates

• Needed to decrease pain for comfort and examination purposes

Bed Rest

• No

• No

• No

• No

Anticoagulation

• Cancer is a hypercoaguable state

• High burden of tumor in metastatic disease

• Possible value in prophylaxis against venous thromboembolism

• If patient not mobile subcutaneous heparin or compression devices is indicated

Prevention of Constipation

• Factors

• Autonomic dysfunction
• Limited mobility
• Opiate analgesic

• Risk of perforation

• Masked by corticosteroids

• Bowel regimen needed

Corticosteroids

Part of standard regimen

• Part of standard regimen

• Limited data on benefit vs. side effects

• Many studies suggesting lower doses can be effective

• No randomized trials

Corticosteroid Recommendations

• High dose dexamethasone and half dose every three days

• Pain with minimal neurological dysfunction can have lower dose

• Small asymptomatic lesions can forgo steroids

Radiation Therapy

Definitive choice

• Definitive choice

• Portal 8 cm wide

• Centered on spine

• Extends one to two vertebral bodies above and below the epidural metastasis

Relieves pain in most cases

• Relieves pain in most cases

• Post-neurological function usually determines response

• Response most associated with tumor type and radiosensitivity; eg. lymphoma

• Dosing 20 to 40 Gy in 5 to 20 fractions

• Popular

• 30 Gy in 10 fractions

Surgery

• Changing role

• Historically posterior vertebral decompression was done

• No survival benefit with or without radiation15

Better techniques today allow aggressive approach

• Better techniques today allow aggressive approach

• Gross spinal tumor resection with vertebral reconstruction now possible

• Experienced surgeon required

Recent controlled trial comparing aggressive surgery followed by radiation vs. radiation alone16

• Recent controlled trial comparing aggressive surgery followed by radiation vs. radiation alone16

• Improvement in surgery+rads

• Days remained ambulatory (126 vs. 35)
• Percent that regained ambulation after therapy (56% vs. 19%)
• Days remained continent (142 vs. 12)
• Less steroid dose, less narcotics
• Trend to increase survival

Chemotherapy

• Can be successful in chemosensitive tumors

• Hodgkin’s lymphoma
• Non-Hodgkin’s lymphoma
• Neuroblastoma
• Germ cell
• Breast cancer (hormonal manipulation)
• Prostate cancer (hormonal manipulation)

Bisphosphonates

• Recommended

• Decrease pathologic fractures in bony disease

• Multiple myeloma
• Breast cancer

Prognosis

• Median survival with ESCC is 6 months14

• Ambulatory patients with radiosensitive tumors have the best prognosis

Treatment Delay

• Education

• EXPERIENCE

• Education

• EXPERIENCE

Case 3: Mrs. HC

• ID: 75 year old female living alone with no significant past medical history

• EC: brought to ER by paramedics after neighbor called b/c she was found in her apartment unresponsive

• No collateral history

Examination

• Fluctuating level of consciousness

• Vitals normal, no fever

• Dehydrated

• Coarse upper airway sounds

• No other pertinent findings

Investigations

• CBC normal

• Mildly elevated BUN and Cr

• Normal LFTs

• Standard electrolytes normal

• Concern of pneumonia

• Chest x-ray ordered……

• Calcium checked

• 4.5

Hypercalcemia

Symptoms

• Usually nonspecific

• Many times patients present with very high calcium level

• Most research done in hyperparathyroidism

Gastrointestinal

• Constipation is most common15

• Exacerbated or confused with narcotic effects
• Related to autonomic dysfunction

• Anorexia

• Vague abdominal pain

• Rarely can lead to pancreatitis

Renal Dysfunction

• Nephrolithiasis

• More common in hyperparathyroidism

• Nephrogenic diabetes insipidus

• Defect in concentrating ability
• Polyuria and polydipsia

• Chronic renal failure

• Longstanding high calcium
• Calcifcation, degeneration, and necrosis of tubules

Neuropsychiatirc

• Anxiety

• Depression

• Cognitive dysfunction

• Delerium
• Psychosis
• Hallucinations
• Somnolence
• Coma

Cardiovascular

• Short QT interval

• Supraventricualr arrhythmias

• Ventricular arrhythmias

Physical Findings

• Usually not specific

• Dehydration secondary to diuresis caused by the hypercalcemia

• Corneal deposition of calcium

• “band keratopathy” on slit lamp exam

Epidemiology

• Occurs in about 10 to 20% of patients with cancer

• Both solid tumors and leukemias

• Most common

• Breast
• Lung
• Multiple myeloma

Pathogenesis

Three mechanisms

• Osteolytic metastases with local cytokine release

• Tumor secretion of parathyroid hormone-related protein (PTHrP)

• Tumor production of calcitriol

Osteolytic Metastases

Breast cancer

• Breast cancer

• Non-small cell lung cancer

• Cytokines released

• Tumor necrosis factor
• Interleukin-1
• Stimulate osteoclast precursor differentiation into mature osteoclasts
• Leading to more bone breakdown and release of calcium

PTH-Related Protein

• Most common in patients with non-metastatic tumors

• Called humoral hypercalcemia of malignancy

• Secretion of PTH itself is a rare event

• PTHrP binds to same receptor as PTH and stimulates adeynylate cyclase activity

• Increased bone resorption
• Increases kidney calcium reabsorption and phosphate excretion

Calcitriol

• Hodgkin’s disease (mechanism in majority)

• Non-Hodgkin’s (mechanism in 1/3)

• Usually responds to glucocorticoid therapy

Diagnosis

Clinical symptomology with

• Clinical symptomology with

• History of cancer
• Risk factors for cancer
• Suppressed PTH

• Some centers can test for PTHrP to confirm Dx of humoral hypercalcemia

• High PTHrP may predict response to pamidronate16

• Less of a response

• Malignancy must be ruled out in patients that present with a very high calcium and no other obvious cause

Treatment

Aims

• Lower serum calcium concentration

• Treat complications if present

• Treat underlying disease

Volume

• Large volume of normal Saline administration

• Expands intravascular volume

• Increases calcium excretion

• Inhibition of proximal tubule and loop reabosrption
• Reduces passive reabsorption of calicum

• Follow fluid status b/c of danger of fluid overload

Inhibition of Bone Resorption

• Three therapies

• Calcitonin
• Bisphosphonates
• Gallium nitrate

• Historical therapy

• Antitumor antibiotic plicamycin (mithramycin)
• Multiple serious side effects
• No longer manufactured

Calcitonin

• Salmon calcitonin

• Increases renal excretion of calcium

• Decreases bone reabsorption by interfering with osteoclast maturation

• Weak agent

• Works the fastest

Bisphosphonates

• Adsorb to the surface of bone hyroxyapatite

• Interfere with osteoclast activity

• Cytotoxic to osteoclasts

• Inhibit calcium release from bone

• Three commonly used

• Pamidronate
• Zoledronic acid
• Etidronate (1st generation, weaker)

Bisphosphonates

• More potent than calcitonin

• Maxium effect occurs in 2 to 4 days

• Trend to use of IV zoledronic acid in the acute situation

• Both are can be renal toxic

• More potent than pamidronate
• Administered over a shorter period of time (15 minutes vs. 2 hours)

Prophylactic Bisphosphonates

• Pamidronate use in patients with known lytic lesions17

• Less episodes of hypercalcemia
• Less pathologic fractures
• Less pain
• Less spinal cord compression
• Less need for radiation or surgery

Newly discovered side effect…

• Osteonecrosis of the jaw

• Recent case reports of jaw bone necrosis in patients on pamidronate

• EDUCATION needed

Gallium Nitrate

• Effective

• More potential for nephrotoxicity

• Rarely used

Dialysis

• Last resort

• Dialysis fluid with little or no calcium is effective

• Useful when patients can’t tolerate large volume resuscitation

• If calcium needs to be correct emergently

Recommendations in symptomatic situation

• Volume expansion

• Salmon calcitonin

• IV zoledronic acid or pamidronate

• Close follow up of calcium level and symptoms

Transitions in Treatment

Chemotherapy

• Two roles

• Direct treatment of cancer

• Palliation of symptoms

Palliative Chemotherapy

• Goal is not cure

• Goals

• Control of tumor
• Preservation of function
• Help tumor symptoms
• Pain
• Dsypnea
• Pruritis
• Poor appetite
• Weight loss

Fine Balance

• Chemotherapy can be very toxic

• Ratio: benefit vs. toxicity

• Host factors and tumor factors

• Delicate balance in palliative situation

• Want medications that affect tumor but do not heavily affect host

Psychology of Cancer

• Psychological evolution during cancer treatment

• Many people have fought very hard with their disease

• Chemotherapy for “relief” not “cure” can be difficult concept for patients

• ART of medicine

Evolution

• Chemotherapeutic protocols that have less side effects

• molecular targeted therapies

• Attack tumor specifically
• Less effect on host

Breast cancer

• Breast cancer

• Colon Cancer

• Prostate cancer

• Lung cancer

Breast Cancer

• Aromatase inhibitors for ER positive tumors

• Anastrozole, Letrozole, Exemestane

• Trastuzumab (Herceptin)

• Humanized monoclonal antibody targeting Her-2/neu protein on breast cancer cells
• Inhibits growth factor signal transduction
• Tolerated quite well

Colon Cancer

• Capecitabine (Xeloda)

• Oral drug that is transformed into 5-FU with three enzymatic reactions

• Final enzyme is at higher levels in tumor cells
• Contributes to drug’s less toxic side effect profile
• Less stomatitis, less myelosupression

Targeted GI Therapies

• Bevacizumab

• Monoclonal antibody to vascular endotheial growth factor receptor
• Some cardiac toxicity

• Cetuximab

• Monoclonal antibody to human epidermal growth factor receptor
• Skin toxicity

Prostate Cancer

• LHRH analogues

• Leuprolide (Lupron)

• Goserelin (Zoladex)

• Stop testosterone production with limited side effects

Lung Cancer

• In stage IV disease patients who receive Cisplatin based doublet chemotherapy live longer and feel better than best supportive care

• Hard to balance side effects

Gefitinib (Iressa)

• Targets epidermal growth factor receptor (tyrosine kinase small molecule inhibitor)

• May have a role in the palliation of advanced non small cell lung cancer patients

Palliative Care Debate

• Do not accept any patient on “active” therapy

• This needs to be further elucidated

• Patients being palliated with chemotherapy or targeted therapies still have other palliative care issues and needs

• Should a patient still on Xeloda for breast or colon cancer not be admitted to St. Boniface 8A?

Thank you

Any questions?

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