Oncologic EmergenciesOncologic Emergencies

Thiti Si i i hThitiya SirisinhaMedical Oncology UnitR thib di H it lRamathibodi Hospital

RCP TRCP , Trang29 July 2552

O liOutline• superior vena cava syndrome• spinal cord compressionp p• metabolic complications

– HypercalcemiaHypercalcemia

• (pericardial tamponade, upper airway obstruction, etc), )

Critical Thinking in Evaluation & M f O l i E iManagement of Oncologic Emergencies

Natural history of the primary tumor

• Is there a previous diagnosis of cancer?• Is there a previous diagnosis of cancer?

• What is the disease-free interval between Dx of primary tumor and onset of emergency condition?

• Has the emergency develop in a setting of terminal diseases?

Critical Thinking in Evaluation & M t f O l i E iManagement of Oncologic Emergencies

Efficacy of available Rx• No prior therapy versus extensive preRxp py p

• Is prompt Rx required to prevent further debilitation?debilitation?

• Will the patient’s medical condition pinfluence the ability to administer effective Rx?

iSuperior Vena Ca aCava SyndromeSyndrome

The Scottish obstetrician and anatomist: complication of a syphilitic aortic aneurysm

Superior Vena Cava Syndrome Si & S tSigns & Symptoms

• classic : facial, arm&neck edema/ plethoraclassic : facial, arm&neck edema/ plethoradyspnea, cough, orthopnea

h h id• others : hoarseness , stridordysphagiah d h di iheadache, dizziness, syncopechest pain, pleural effusion

• usually insidious onset• usually worsens by lowering of the heady y g

Facial swelling associated with SVC Syndrome in a patient with malignancySy d o e a pat e t t a g a cy

.

The Pemberton signThe Pemberton Sign

Wallace, C. et. al. Ann Intern Med 1996;125:568-569

EtiologyEtiology

• Before antibiotics the most common causes• Before antibiotics the most common causes were from complications of untreated infectioninfection– Syphilitic thoracic aneurysms

fib i di i i i– fibrosing mediastinitis

• Malignancy is presently the most common cause

Etiologyt o ogyNON

EO

Lung Cancer 68% N

O

ON

N

SVC thrombosis

TB di ti itiOPLA

Lymphoma 6%

Others 9%

O

N

NEOP

TB mediastinitis

S hilitiAST

Others 9%• Metastatic CA

•Breast CAG C ll t

PLAS

Syphilitic aneurysm

Hi t l iIC

•Germ Cell tumor TIC

Histoplasmosis

Radiation fibrosisRadiation fibrosis

Lung CancerLung Cancer

i i i di i i• extrinsic compression or direct invasion– primary tumor or by enlarging mediastinal

nodesnodes

• 20% of small cell lung cancer vs 2-4% of % g %NSCLC develop SVC obstruction

• SCLC tends to occur centrally in contrast to other types

LymphomaLymphoma• predominantly non-Hodgkin’s lymphomap y g y p

• Hodgkin’s rarely causes SVC syndrome

• Extrinsic compression caused by enlarging lymph nodes

• diffuse large cell and lymphoblastic are most commonly associated with SVC syndrome y y– different Rx approach precise diagnosis is important

DiagnosisTi l id ifi i f h i i l• 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 pdiagnosis of cancer6

– Need a tissue biopsy for histologic studiesp y g

66. Schraufnagel, DE, Hill, R, Leech, JA, Pare, JA. Superior vena caval . Schraufnagel, DE, Hill, R, Leech, JA, Pare, JA. Superior vena caval obstruction. Is it a medical emergency?. Am J Med obstruction. Is it a medical emergency?. Am J Med 19811981; ; 7070::11691169. .

Diagnostic Procedures and Yield in SVC SyndromeSVC Syndrome

procedure positive yields (%)

CXR 84sputum cytology 49sputum cytology 49 LN biopsy 67 thoracenthesis 71thoracenthesis 71bone marrow 23 bronchoscopy 52bronchoscopy 52 thoracotomy 98 mediastinoscopy 81 py

CXR FindingsCXR Findings• Most patients have an abnormal chest x• Most patients have an abnormal chest x-

ray at presentation

• superior mediastinal widening 64%• pleural effusion 26%• pleural effusion 26%• right hilar mass 12%

anterior mediastinal mass 3%• anterior mediastinal mass 3%• normal 16%

CT Chest

• Preferred choice

• IV contrast d fi th l l f b t ti– defines the level of obstruction

– Maps out collateral pathwaysid if d l i f b i– Can identify underlying cause of obstruction

Superior Vena Cava SyndromeM thMyths

• emergent treatment is needed even before diagnosis is established

• excessive complications from diagnostic procedures usually arise if the obstruction is

t li d fi tnot relieved first

• radiation is not harmful if given to benign g glesion

Superior Vena Cava Syndrome

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

• Standard of care was immediate radiotherapyStandard of care was immediate radiotherapy– Zap now– Ask questions later– Ask questions later

• The emergent approach is not appropriate for most patients

Emergent to UrgentEmergent to Urgent• Symptomatic obstruction is usually a y p y

prolonged process

• Most patients are not in immediate danger• Most patients are not in immediate danger at presentation

M t h ti f f ll di ti k• Most have time for a full diagnostic work up

• Prebiopsy radiation can obscure the p ydiagnosis

Conditions that need emergency treatment in SVC syndrome

• Airway obstruction• Increased intracranial pressure• Increased intracranial pressure• Cardiovascular collapse

Histologic Diagnosis

• Essential

• Guides treatment

• Aids in defining prognosis

SVC Syndrome : yGeneral Management

• definitive treatment depends on the etiology• medical adjuncts to relief symptoms• medical adjuncts to relief symptoms

– Elevate head of bedO– Oxygen

– Diuretics?– Steroids? airway edema

• Avoid IV in the arms

Superior Vena Cava Syndrome : Treatment

• chemotherapy may be a treatment of choice if• chemotherapy may be a treatment of choice if tumor is chemosensitive – small cell lung cancer small cell lung cancer

– lymphoma

– Germ cell tumor

• Can achieve long term remission with tumor specific directed therapyspecific directed therapy

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

Superior Vena Cava Syndrome :

• radiation usually can provide relief for other

Treatmentradiation usually can provide relief for other tumors that don’t respond to chemotherapy– NSCLC

• SVC obstruction is a strong predictor of poor i i NSCLCprognosis in NSCLC

• Note: improvement in systemic Rx of many• Note: improvement in systemic Rx of many cancers results in prolongation of survival – NSCLC, breast CA

Superior Vena Cava Superior Vena Cava S dS dSyndromeSyndrome

before treatment after treatment

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• Patient too ill to tolerate radiation or chemotherapy

T d t id id li f f t• Tends to provide more rapid relief of symptoms

• Issue of anticoagulation after is not resolved

Spinal Cord pCompression

The Classic Storyy

• 56 year old man56 year old man • one month history of back pain that is not

responding to Tylenolresponding to Tylenol– Pain beginning to wake him at night

M i ith b– More pain with recumbency– Some shooting pains down right leg

• ROS: negative

On examination• Back exam

– Inspection: normalInspection: normal– Palpation: some pain in L1– ROM: normal

S i i i ht l ith t i ht l i i– Some pain in right leg with straight leg raising• Lumbar Spine X-ray

– Some age related degenerationSo e age e a ed dege e a o

• Sciatica vs. Back strainT t t• Treatment: – NSAIDS– Few days of bed resty

The story continues…• pain does not resolve & more trials of various

forms of pain control failp

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

• Patient has objective leg weakness on physical examexam

• A very keen medical student does a rectal exam d di l d l t tand discovers a large nodular prostate

• PSA: 45.0

Problem and ImpactProblem and Impact

F il f i i• Failure of recognition– Presentation can be very subtle

• Early diagnosis and treatment are imperative– Most important determinant of neurological p g

outcomes is the degree of neurological impairment at the time of Rx initiation

CausesCauses• Metastatic tumor from any primary sitey p y• Tumors with predilection to metastasize to

spinal columnspinal column• Prostate, breast, and lung carcinoma

15 20% of cases– 15-20% of cases• Renal cell, non-Hodgkin’s lymphoma, or

lmyeloma– 5-10% of cases

• vertebral body or pedicle : 85%• vertebral body or pedicle : 85%• intervertebral foramina : 10%• intramedullary : 4%intramedullary : 4%• epidural space : 1%

Spinal Location

• Thoracic spine: 60%• Lumbosacral spine: 30%Lumbosacral spine: 30%• Cervical spine: 10%

• Specific tumor predilection is difficult to define

Diagnosis Needs High Level of SuspicionSuspicion

Red flag : Beware of pain ifRed flag : Beware of pain if….• Sudden change of longstanding back pain• Crescendo pattern of pain• Crescendo pattern of pain• Worse lying down• Exacerbate by coughing sneezing straining• Exacerbate by coughing, sneezing, straining• radiculopathy

~ 60% of patients with new back pain, abnormal plain film and normal neuro. exam have epidural cord compression~ 60% of patients with new back pain, abnormal plain film and normal neuro. exam have epidural cord compression

Other Clinical Presentation

• Weakness– Weakness tends to be symmetrical– Progressive weakness is followed by lost of

gait function then paralysis– The severity of weakness is greatest with

thoracic metastasesthoracic metastases

• Sensory: – Ascending numbness and paresthesia

• Bowel & bladder dysfunction : late signs

Spinal Cord Compression

• differential diagnosis– Compression fracture (pathologic, osteoporotic)p (p g , p )– epidural abscess– hematomahematoma– herniated discs

leptomenigeal disease– leptomenigeal disease– radiation myelopathy / intrethecal

chemotherapychemotherapy

Prognosis• Early recognition leads to better outcomes

g

• prognosis depends on – degree of neuro. deficit at time of diagnosis– duration of symptoms

• Median time from symptoms to diagnosis is around 2 h 1months1

• More than half of patients who present to hospital are b l tnon-ambulatory

11. Husband, DJ. Malignant spinal cord compression: Prospective study of delays in . Husband, DJ. Malignant spinal cord compression: Prospective study of delays in 11. Husband, DJ. Malignant spinal cord compression: Prospective study of delays in . Husband, DJ. Malignant spinal cord compression: Prospective study of delays in referral and treatment. BMJ referral and treatment. BMJ 19981998; ; 317317::1818. .

Outcome of Patients with S i l C d C iSpinal Cord Compression

status at Dx % of ambulatory pts after Rx

ambulatory 98%ambulatory 98%

non-ambulatory 60%

paraplegic 11%

f ll l i > 48 h i ll t ibl

M Z E I t J R di t Bi l Ph 32 959 1995

full paraplegia > 48 hrs is usually not reversible

MaranZano E, Int J Radiat Biol Phys 32: 959,1995

Diagnostic Evaluationg• MRI has replaced myelogram and is now a gold

standardstandard – CT myelography involves a lumbar puncture

and is contraindicated in brain metastases, thrombocytopenia, or coagulopathy

• Entire imaging of spine is ideal

• Other less informative investigation– Plain x-rayy– Bone scan: more sensitive than x-ray, images

entire skeleton

Plain Spine Radiographsp g p• Easiest and cheapest

– detect abnormality in 72%

• Need large bony destruction or vertebral collapse to be diagnostic : loss of pedicle

• High false negative rate

• Not recommended to confirm diagnosisg

MRI• Gold standard• Images whole spine with high resolution• Differentiates bone fragment compression vsDifferentiates bone fragment compression vs

tumor compression• Localie lesion for radiation planning• Localie lesion for radiation planning

• Patients in pain must lie still

Treatment Objectives

• Pain control• Avoidance of complicationsAvoidance of complications• Preserve or improve neurological function

L l/ l• Local/ tumor control

• full paraplegia > 48hrs is usually not reversible

Spinal Cord CompressionTreatment: Steroids

• start steroid once suspected while awaiting further diagnostic procedures

d d f i• reduce edema from compression• Dexamethasone 10 mg followed by 4-8 mg q

6 h (d i d b t bl )6 hr (dose is debatable)• Pain with minimal neurological dysfunction

can have lower dosecan have lower dose• Half dose every 3-4 days during radiation

Spinal Cord CompressionRadiation TherapyRadiation Therapy

• radiation is the standard initial treatment for most patients and should begin emergently

• Relieves pain in most casesRelieves pain in most cases

• preRx-neurological function usually determines responseresponse

• Response often is associated with tumor type and di iti it L hradiosensitivity; eg. Lymphoma

• Dosing 30 Gy in 10 fractions

Spinal Cord CompressionTreatment : SurgeryTreatment : Surgery

• if never been Dx with cancer and no other obviousif never been Dx with cancer and no other obvious sites of cancer needs open surgical biopsy +/-decompression

• Other indication for surgery : – tissue diagnosistissue diagnosis– decompression in patients previously irradiated – spinal instability– Bony compression of cord– worsened neurologic deficits during radiation

Spinal Cord CompressionTreatment : Surgery

• Changing role• Historically posterior vertebral y p

decompression (laminectomy) was done– No survival benefit with or without radiationNo survival benefit with or without radiation

• Recent study (Patchell 2003) : aggressivesurgery (gross spinal tumor resection) +RTsurgery (gross spinal tumor resection) +RT is better than RT alone

Gross Spinal Resection/RT vs RTP h ll 2003

• Improvement in surgery+radiation

Patchell 2003• Improvement in surgery+radiation

– Days remained ambulatory (126 vs. 35)P t th t i d b l ti ft th– Percent that regained ambulation after therapy (56% vs. 19%)Days remained continent (142 vs 12)– Days remained continent (142 vs. 12)

– Less steroid dose, less narcoticsT d t i i l– Trend to increase survival

Patchell, R, Tibbs, PA, Regine, WF, et al. A randomized trial of direct decompressive surgical Patchell, R, Tibbs, PA, Regine, WF, et al. A randomized trial of direct decompressive surgical resection in the treatment of spinal cord compression caused by metastasis (abstract). proc Am Soc Clin Oncol 2003; 22:1.

Spinal Cord CompressionTreatment: chemotherapy

C b f l i h iti t• Can be successful in chemosensitive tumors– Hodgkin’s lymphoma– Non-Hodgkin’s lymphoma– Neuroblastoma– Germ cell– Breast cancer (hormonal manipulation)– Prostate cancer (hormonal manipulation)

H percalcemiaHypercalcemia

Epidemiologyp gy

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

h lid d l k i• Both solid tumors and leukemias• Most common

– Breast– Lungg– Multiple myeloma

HypercalcemiaHypercalcemia

severity of symptoms depends on• severity of symptoms depends on – calcium level :

corrected calcium level corrected calcium level =measured ca++ + [0.8 x (4 - albumin )]

rate of rise of calcium– rate of rise of calcium

• patient’s symptomatology is more relevant• patient s symptomatology is more relevant than absolute calcium level

Clinical ManifestationsClinical Manifestations• Symptoms usually non-specific

• Mild symptoms• Severe symptoms

Gross dehydration– Nausea– Lethargy

– Gross dehydration– Drowsiness– Confusion and coma

– Anorexia and vomiting– Constipation

Thirst and polyuria

– Abnormal CNS– Cardiac arrhythmias

– Thirst and polyuria • Shortened QT• Shortened PR• Wide T waveWide T wave

Three mechanismsThree mechanisms

• Osteolytic metastases with local cytokine• Osteolytic metastases with local cytokine release

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

• Tumor production of vitamin D/ calcitriol

1. Osteolytic Metastasesy

• Local cytokines releasedy– Tumor necrosis factor– Interleukin-1, IL-6, osteoclast activating factor– Stimulate osteoclast precursor differentiation

into mature osteoclastsL di b b kd d• Leading to more bone breakdown and release of calcium

• Common CA : breast CA, myeloma, NSCLC (non squamous)

2. PTH-Related Protein Humoral Hypercalcemia of MalignancyHumoral Hypercalcemia of Malignancy

• common in patients with no bone metastasis

• PTHrP binds to same receptor as PTH (close homology) and stimulates adeynylate cyclase

ti itactivity – Increased bone resorption– Increases kidney calcium reabsorption and phosphate y p p p

excretion

• Test not available in ThailandTest not available in Thailand• Suppressed/ low PTH level

Hypercalcemia of Malignancy

• incidence varies with types of cancer– lung cancer : squamous and large cell >> smalllung cancer : squamous and large cell small

cell– Squamous cell carcinoma (head and neck, NPC, q ( , ,

skin)– metastatic breast cancer– Renal cell CA, bladder CA

3. Calcitriol Production by Tumor

• Hodgkin’s disease (mechanism in majority)

• Non-Hodgkin’s (mechanism in 1/3)

• Usually responds to glucocorticoid therapy

Hypercalcemia: Evaluation

• correct total ca++ conc. for serum albumin

• evaluate volume status and renal function

• determine the stage of cancer and whether there is specific treatment options for it

• consider non-malignant causes

• Most patients with hypercalcemia of malignancy have advance disease and rarely “occult tumor”occult tumor

Hypercalcemia of Malignancy Basic Treatment ConsiderationBasic Treatment Consideration

• short term treatment will almost always lower yserum ca++ in most cases

• extracellular fluid volume should be expanded to pinduce caliuresis

• Ca lowering agents should be used on a case g gper case basis

• antitumor Rx should be employed for best long p y gterm result

• Should the Rx be withheld if the patient is pterminal with limited chance of response to antitumor Rx?

VolumeVolume• Large volume of normal saline administration• Expands intravascular volume• Increases calcium excretionIncreases calcium excretion

– Inhibition of proximal tubule and loop reabosrptionreabosrption

– Reduces passive reabsorption of calicum• Follow fluid status b/c of danger of fluid• Follow fluid status b/c of danger of fluid

overload

Hypercalcemia of MalignancyHypercalcemia of MalignancyTreatment: Calcium Lowering Agent

–calcitonin–bisphosphonates

steroids–steroids

CalcitoninC c o

• Salmon calcitonin• Salmon calcitonin• Increases renal excretion of calcium

D b b ti b i t f i• Decreases bone reabsorption by interfering with osteoclast maturationW k t• Weak agent

• Works the fastest (within 4-6 hr) , t h h l i ft f d (>48 h )tachyphylaxis after few doses (>48 hr )

• Dose 4-8 unit/ kg SC/ IV every 12 hr

Bisphosphonatesp p• Adsorb to the surface of bone hydroxyapatite• Interfere with & cytotoxic to osteoclast • Inhibit calcium release from bone• Very long half-life in bones ,accumulates at

sites with active bone turnoversites with active bone turnover• Poor GI absorption

M h l i i• More potent than calcitonin

Bisphosphonatesp p• Maxium effect occurs in 2 to 4 days• Duration of response varies usually ~ 2 4 weeks• Duration of response varies, usually ~ 2-4 weeks• To be given following volume replacement• Two commonly used agents• Two commonly used agents

– PamidronateZoledronic acid– Zoledronic acid• More potent than pamidronate• Administered over a shorter period of time (15Administered over a shorter period of time (15

minutes vs. 2 hours)• Both can be renal toxic, cautious use if Cr> 4.5,

Newly discovered side effect…

• Osteonecrosis of the jaw

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

• creatinine should be checked

THE ENDTHE END