Oncological Emergencies Dr. Gary Harding md, frcpc



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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

  • 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



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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