2. CANCER BURDEN
• In 2000, burden of new case estimated 10.1 million
• 56 % of cancer deaths in developing countries
• Lung cancer >> stomach ca > prostate, colorectal ca
• Develpoed countries : breast >> colorectal > lung > uterus
• Males : lung > stomach> liver > H&N
• Females : breast, cervix > stomach> lung > colorectal
BURDEN IN INDIA
• 2 – 2.5 million cases at a given time
• Year 2000 : 8 lakh new cases, 5.5 lakh deaths
• Heavy tobacco use : leading cause
• 70 % present at advanced stages ( T3 – T4 stages ) : heavy
( MOHFW and TMH EBM data )
3. • Any cancer may present itself as an emergency
due to :
mass effect ( SVC syndrome, cord compression,
leucostasis , gut obstruction etc.)
Tumor invasion ( sentinal/ torrential bleed,
effusions and tamponade )
Paraneoplastic syndrome ( hypercalcemia,
SIADH, etc. )
Chemo induced damage ( heart failure,
pancreatitis, severe infections, renal and hepatic
failure , etc. )
4. Considerations before intervention
• Is the condition truly emergent ?
• malignancy or a benign process ?
• Specific tumor type ?
• Tumor stage ?
• Studies required to establish diagnosis ?
• Prognosis and impact of intervention on patient ?
• WHAT ARE THE WISHES OF THE PATIENT AND
Irvin & Rippe, 7th edition
6. 1. TUMOR LYSIS SYNDROME
• Syndrome of metabolic derangements
• Observed in cancers with large tumor burden,
high proliferative rates or high chemosensitivity.
• Metabolic derangement due to massive cell lysis
and outpouring of intracellular chemicals:
• most frequently in patients with NHL and other
hematologic malignancies,particularly Burkitt’s
lymphoma, ALL, and acute myeloid leukemia (AML).
• The overall incidence of LTLS and CTLS ranges from
• 14%-17% and 3%-5% in AML,
• 21%-30% and 5%-8% in ALL,
• and 19%-40% and 6%-20% in NHL
• solid tumors : occurrences are rare, with a very high
mortality ( 1 in 3 )
• currently no universally accepted system for
classification and grading.
• The most recent and preferred is : Cairo and Bishop
• based on defining laboratory or clinical TLS (LTLS or
• This system distinguishes between patients who do not
require therapeutic intervention versus those
experiencing life-threatening clinical abnormalities.
• LTLS is considered to be either present or absent,
• whereas the grade of CTLS is defined by the maximal
grade of the clinical manifestation
12. Clinical manifestations
• may occur before the start of chemotherapy
• observed more commonly within 12 to 72 hours after the initiation of
• nausea, vomiting, diarrhea,
• edema, fluid overload, congestive heart failure,
• cardiac dysrhythmias,
• muscle cramps, tetany,
• syncope, and possible sudden death.
• Complications can compromise the efficacy or further administration of
HIGH RISK PATIENTS
• Adequate hydration and urine output are of
high importance in preventing TLS
• should be admitted to an intensive care unit
• rasburicase should be used in the initial
management of pediatric patients
• Delaying tumor therapy
• RRT as required
15. INTERMEDIATE RISK PATIENTS
• allopurinol may be used
• single dose of rasburicase might also be
considered in pediatric patients
LOW RISK PATIENTS
• watch-and-wait approach
17. FLUIDS AND HYDRATION
• Aggressive hydration and diuresis are fundamental to the
prevention and management
• Promotes the excretion of uric acid and phosphate by
improving intravascular volume, RBF, and GFR.
• Vigorous hydration is recommended for all patients in the
intermediate to- high risk groups
• Fluid intake should be maintained at approx 1-2 times
maintenance, with a urine output of 80 to 100 mL/m2/h
• currently not recommended
• risk of precipitation of calcium phosphate crystals
• only indicated for patients with metabolic acidosis, in which
case sodium bicarbonate may be considered based on the
standards of the institution.
• competitive inhibitor of xanthine oxidase
• Use of allopurinol has been shown to decrease the formation of
uric acid and to reduce the incidence of obstructive uropathy
• ORAL : 50 to 100 mg/m2 every 8 hours (maximum dose, 300
mg/m2/d) or 10 mg/kg/d divided every 8 hours (maximum dose,
• IV : 200 to 400 mg/m2/d in one to three divided doses (maximum
dose, 600 mg/d).
• initiated in intermediate risk patients no more than 12 to 24 hours
before the start of induction chemotherapy UPTO 3-7 DAYS AFTER
• be continued until uric acid levels are normalized, and tumor
burden, WBC count, and other laboratory values have returned to
low-TLS risk levels
19. • only prevents the formation of uric acid and does not reduce uric
acid produced before the initiation of treatment. patients with
pre-existing severe hyperuricemia (> 7.5 mg/dL), treatment with
rasburicase is preferred
• Allopurinol can also cause an increase in serum levels and crystal
deposition of the purine precursors xanthine and hypoxanthine,
which can result in acute obstructive uropathy.
• In addition, because allopurinol also reduces the degradation of
other purines, particularly 6- mercaptopurine, dose reductions of
50% to 70% of 6-mercaptopurine and/or azathioprine are
• Because allopurinol is excreted by the kidneys, a dose reduction of
50% is recommended in patients with renal insufficiency.
• Urate oxidase converts uric acid into allantoin, which is five to 10
times more soluble in urine than uric acid
• recommended for the treatment of patients with hyperuricemia
associated with LTLS or CTLS, or in the initial management of
patients considered to be at high risk
• 0.15 to 0.2 mg/kg once daily , as an IV infusion over 30 minutes for
• However, rasburicase has demonstrated activity even at lower
doses and for shorter duration.
• Therefore, a dose of 0.10 to 0.2 mg/kg daily, dependent on whether
the intention is prevention or treatment may be used
TIMING AND DURATION
• 1 to 7 days
• uric acid levels be monitored regularly
• rare , include anaphylaxis, rash, hemolysis,
methemoglobulinemia, fever, neutropenia
(with or without fever), respiratory distress,
sepsis, and mucositis.
• contraindicated in patients with a known
G6PD deficiency and in pregnant or lactating
• rasburicase will cause the degradation of uric
acid within blood samples : assay, which is
preferably done within 4 hours of collection.
• eliminating phosphate from IV solutions,
• maintaining adequate hydration,
• administration of phosphate binders.
• Aluminum hydroxide 50 to 150 mg/kg/d is administered in divided
doses orally or nasogastrically every 6 hours.
• Its use should be limited to 1 to 2 days to avoid cumulative
• other phosphate binders : such as calcium carbonate, sevelamer
hydroxide, and lanthanum carbonate
For severe hyperphosphatemia,
• RRT : hemodialysis, peritoneal dialysis, or continuous venovenous
hemofiltration has been used
• Phosphate clearance was found to be better with hemodialysis as
compared with continuous venovenous hemofiltration or peritoneal
24. MONITORING DURING TREATMENT
• Check laboratory and clinical TLS parameters 4 to 6 hours after the initial
administration of chemotherapy.
• The TLS parameter consists of :
fluid input and urine output
• Uric acid levels should be re-evaluated 4 hours after administration of rasburicase
and every 6 to 8 hours thereafter until resolution of TLS
• If TLS has not occurred after 2 days, the likelihood is essentially zero that the
patient will experience TLS
• Approx 3% require RRT.
• Nephro consultation be obtained immediately if :
oliguria or anuria,
if there is persistent or elevated urea (> 150mg/dl), phosphate(>10mg/dl) or
potassium levels(>7mmol/L), or life threatening hypocalcemia
in spite of optimal conservative measures
27. • MECHANISMS IN MALIGNANCY :
1. Direct osteolysis by tumor
2. Increased osteoclastic resorption
3. Renal insufficiency
PTHrP : Plays a role , elevated in 80 % patients.
• Acitivity similar to PTH.
• Stimulates osteoblasts production of RANKL
osteoclasts activation osteolysis & production of
bone derived growth factors ( TGF β, IGF-1) TUMOR
CELL PROLIFERATION AND MORE PRODUCTION OF
PTHrP renal resorption increases in DCT
• In some lymphomas, there is raised levels of Vit D
metabolites increased gut absorption
33. • Decision to treat depends upon :
Patient and family wishes
• INITIAL THERAPY OF CHOICE
• May require upto 3-7 litres/ 24 hrs
• Loop diuretics to be used ONLY if CHF is a concern
• IF DIURETICS USED PRIOR TO REPLETION :
HYPERCALCEMIA CAN WORSEN.
34. 2. Biphosphonates
• Most useful agents
• Prevent osteoclastic bone resorption : inhibit
prenylation of GTP, also are cytotoxic to osteoclasts.
• BPN approved : Zoledronate , pamidronate
• Comparative studies indicate : improved response rates
• Dose : 4 mg , IV, over 5 min
• 8mg : for refractory hypercalcemia
• Effects appears in 3-4 days, peaks in 7-10 days , lasts for
2 weeks- 2 months
• ADR: const. symps, fever, hypophosphatemia,
35. 3. Calcitonin
• Inhibits bone resorption, reduces renal
• Source : salmon calcitonin
• Dose: 4 IU/kg, SC/IM, every 12 hrs
• Tachyphylaxis develops rapidly
• Efficacy limited to 24-48 hrs.
• Effective in MM and lymphomas : cytotoxic
• Onset is slow, develops over weeks
• MOA : suppression of tumor and reduced gut
absorption of calcium.
36. 4. RANKL antibody
• Denosumab : monoclonal ab, interferes with
5. Decoy RANKl ligand , osteoprotegerin
No RCTS for above agents.
6. RRT : considered for severe and refractory
• Development in lung ca : suggestive of
unresectability, poor prognosis
• 20 % MM presents with hypercalcemia :
represents adv ds. , poor prognosis
• Those with other solid tumors : grim survival,
median survival 30-60 days.
• Malignant cause
1. Lung ca : small cell ca (m.c. )
– 34 % > squamous ca ( 21 %)
> adenoca (14 % )
2. Lymphoma : NHL ( 13 %) > HL
( 0.8 % )
3. Others ( 6 %)
• Non malignant cause
• Idiopathic mediastinal fibrosis
• Prior radiation
40. Signs and symptoms
• Depends upon the acuity of obstruction :
• no time for collateral formation
• Venous hypertension cause symptoms : cough, dypnea,
edema of H&N
• Rarely : hoarseness, headaches, chest pain, dysphagia
• Plethora, edema of H& N
• JVP distension
• Rarely, papilledema and stridor.
• Initial investigation : CXR, CECT
• Venography or MRI : to better define extent of obstruction
• Aim to achieve tissue diagnosis at the earliest : sputum
cytology, BAL, thoracoscopy, FNAC, LN Bx, mediastinoscopy,
VATS, Open thoracotomy.
• In those with established diagnosis
• 30 Gy in 10 fractions : m.c.
• Curative intent : 50 Gy in 25 fractions
• In chemosensitive tumors : germ cell ca, small cell lung ca,
• For those who lack tissue diagnosis
• For emergency palliation of symptoms
• Responses are durable ( 90% symptom free vs . 12 % with RT )
• Reserved for benign disease
• In those with tracheal obstruction with resistance to CT/RT.
• In small cell ca and lymphomas : not a
predictor of negative outcome
• In these patients , curative intent is adviced.
44. 4.EPIDURAL CORD COMPRESSION
• Compression of dural sac
and contents by extradural
mass ( primary or met )
• M.c. : vertebral body
• Site : thx (70%) > lumbar
(20%) > cx (10%)
• Lymphomas cause cord
compression and IV
foramen invasion without
clinical compression :
normal films, normal
46. Signs and symptoms
• Cardinal sign : pain ( 95%)- worsens on
coughing, straining ; radicular distribution
• Autonomic dysfunction
• Sensory deficit
• Urinary retention : late presentation
• Duration between pain and paralysis : variable
; 24-48 hrs to years
MRI : primary modality
• More sensitive for paraspinal ds.
• Has helped in defining extent of
RT. ( clincally assessed had plan
changed in 53 % ).
• Better delineation of level of
CT : faster than MRI ( in
• Superior for vertbral body
• Useful prior to surgical
• In emergent situations, awaiting MRI
• Reduction in peritumoral edema
• High dose dexa : 100 mg bolus,thn, 96mg/d, tapered over 2 weeks
• Or, 10 mg IV, then , 4mg/QID, taper over 2 wk
• In highly radiosensitive tumors : first line
• With multiple levels of involvement
• Paraplegia for > 48 hrs.
• Age > 65 yrs : sx associated with morbidity in elderly
• Dose : 30 Gy , 10 fractions over 2 weeks (m.c.)
• RT vs. RT + Sx : pt. with combination were mobile ( 84% vs 57 %)
and ambulatory for longer periods ( 122 days vs 13 days )
• Statistically sign outcome in combination of RT + Sx.
• Those paraplegic at presentation: 10 -19 %
recover ambulation after RT alone vs. 62 % in
those having Sx decompression upfront.
• Early intervention : vital
• Those ambulatory on presentation : 80 %
50. 5. LEUCOSTASIS
• Hyperleucocytosis : defined
as leucocytes > 1 lakh/µL
• Theories :
Adhesion of leucocyted to
Expression of CD56/NCAM
on AML blasts : correlates
with development of
• Most common : AML ( 10 -20 %)
• Probably due to : large size and more adhesiveness of AML
• Risk factors for development :
Total WBC counts
% of blasts
Rate at which counts rise
Lichtmann and Rowe : demonstrated that “LEUCOCRIT” ,
was closely related to development of leucostasis
Leucocrit was proportional to number to circulating
leucocytes and blasts.
52. Clinical manifestations
• Obstruction of vascular beds
• Tissue hypoxia cytokine release
thrombosis organ dysfunction
• Important capillary beds : CNS, RS, Renal,
Coronaries involved by the rigid blasts.
• Viscosity is seldom elevated : since RBCs are
low due to marrow involvement
• Hydroxyurea : 20-30 mg/kg, requires 1-2 days
to take effect.
• RBC transfusions to be avoided until TLC <
50,000 to avoid ischemic events
• leucopheresis : dose of 140 ml/kg ( 2 bld vol )
• Studies have failed to show significant benefit
• It is contraindicated in APML : risk of DIC,
shock and death
• No significant difference in complete response
rates, disease free interval or survival rates in
AML +/- leucostasis
• Pulm. Leucostasis, hepatomegaly,
hyperbilirubinemia, hypofibrinogenemia :
predictors of poor outcome
55. 6. Malignant cardiac tamponade
• Fluid accumulation impairs LV
expansion and diastolis filling.
• SV reduces – tachycardia
• Pressure equalizes in left & right
• Tamponade develops when
pericardium fails to expand : due
to rapid fluid accumulation or
• Pericardial involvement : 1 – 20 %
• Lung, breast, lymphoma , leukemia
• Pericardial effusions in cancer due to :
Pericardial involvement ( 60 %)
Idiopathic pericarditis (32 %)
Radiation induced pericarditis (10 %)
• Other causes : Dressler syndrome , RA,
• Type I : more serious, permanent myocardial damage e.g. doxorubicine
• Type II : reversible usually e.g. trastuzumab
• Acute onset : rare form . may occur immediately after a single dose or a
course of anthracycline therapy, with clinical manifestations occurring
within a week of treatment.
• These may be in the form of transient electrophysiological abnormalities,
Sinus tachycardia is the most common
• Subacute : within days or weeks after completion of chemotherapy ,
results in acute failure of the left ventricle, pericarditis or a fatal
pericarditis-myocarditis syndrome in some rare cases.
• Chronic ( early onset, progressive ) : common and clinically important,
presents within a year of treatment. It may persist or progress even after
discontinuation of anthracyclines therapy, and may evolve into a chronic
dilated cardiomyopathy in adult
• Late chronic : causes ventricular dysfunction , heart failure and arrhythmia
years to decades after chemotherapy has bee completed.
Douraid K. Shakira, Kakil I Rasulb : J Clin Med Res
63. RISK FACTORS
• cumulative dose ( Cumulative doses of doxorubicin as low
as 228 mg/m2 have shown to increase after-load or
• intravenous high single dose,
• time of drug infusion <30 min,
• history of prior irradiation,
• use of other concomitant agents such as
cyclophosphamide, trastuzumab, paclitaxel
• female gender,
• Extremes of age,
• Underlying cardiovascular disease,
• increase in time elapsed since therapy administration.
1. Free radical–mediated myocyte damage : most thoroughly studied
mechanisms in anthracyclines
• The myocardium is more susceptible to free radical damage than other
tissues because it has comparatively
less superoxide dismutase and catalase activity,
and its major defense, glutathione peroxidase, is suppressed by
• free radicals accumulate and cause severe lipid peroxidation, leading to
extensive destruction .
2. Circulating pro-inflammatory cytokines : Doxorubicin induces the release
of histamine and TNF-α from macrophages and interleukin-2 from monocytes
• These cytokines have functional receptors on the myocardium and their
release may result in dilated cardiomyopathy.
3. Adrenergic dysfunction and down regulation of myocardial histamine
and β-adrenergic receptors has also been proposed as a cause for an evolving
and established anthracycline–induced ventricular dysfunction
66. • Periodic monitoring : 2 DEcho is suggested especially for
anthracyclines and their derivates, or monoclonal antibodies.
• Baseline clinical and ECG evaluation are recommended in all
patients undergoing anthracycline therapy [III, A].
• Assessment of baseline systolic and diastolic cardiac function with
DEcho should be conducted before treatment with monoclonal
antibodies [III, A] or anthracyclines and their derivates in patients
aged >60 years, or with cardiovascular risk factors
• Further evaluations of LVEF are recommended, even in
asymptomatic patients, according to the follow timing:
after administration of half the planned dose of anthracycline, or
after administration of cumulative dose of doxorubicin 300 mg/m2,
epirubicin 450 mg/m2 or mitoxantrone 60 mg/m2 [III, A] or
after administration of a cumulative dose of doxorubicin of 240
mg/m2 or epirubicin 360 mg/m2 in patients aging <15 years or >60
years [III, B];
before every next administration of anthracycline [III, A];
after 3, 6 and 12 months from the end of therapy with
anthracycline [III, B].
MANAGEMENT & TREATMENT GUIDELINES (
ESMO , 2010 )
67. • During the echocardiographic assessments, patterns of
PW Doppler of LV inflow tract and TDI-PW Doppler of
mitral anulus should also be evaluated to detect initial
signs of LV dysfunction that might occur before
reduction of LVEF.
• Periodic monitoring (every 12 weeks) of cardiac
function is also suggested for those patients receiving
monoclonal antibodies, especially if previously treated
with anthracycline [III, A].
• Assessment of cardiac function is recommended 4 and
10 years after anthracycline therapy in patients who
were treated at <15 years of age [III, B], or even at age
>15 years but with cumulative dose of doxorubicin of
>240 mg/m2 or epirubicin >360 mg/m2 [III, B].
68. • LVEF reduction of ‡20% from baseline despite normal function or
LVEF decline <50% necessitate reassessment or discontinuation of
therapy and further frequent clinical and echocardiographic checks.
• Aggressive medical treatment of those patients, even
asymptomatic, who show LV dysfunction at 2DEcho after
anthracycline therapy is mandatory, especially if the neoplasia could
have a long-term survival : ACE inhibitors and b-blockers and the
earlier HF therapy is begun (within 2 months from the end of
anthracycline therapy), the better the therapeutic response
• role for biomarkers of cardiotoxicity is not well defined enough to
include them as routine screening measurements.
• a useful approach, even if rather costly and still controversial, is
performing baseline assessment of biomarker concentrations and
periodic measurements during therapy (at the end of
chemotherapy administration, after 12, 24, 36, 72 h and 1 month
later for troponin I; at the end of medicament infusion and after 72
h for BNP) to identify patients who need further cardiac assessment