Management of oncology emergencies

1. MANAGEMENT OF ONCOLOGIC
EMERGENCIES
Moh’d sharshir, MD
Fellow of medical oncology
King Hussein cancer center
29th April, 2011

2. TUMOR LYSIS SYNDROME :

3. TUMOR LYSIS SYNNDROME :
 Oncologic emergency caused by massive lysis of tumor
cells resulting in release of potassium, phosphate and
uric acid into the circulation resulting in life threatening
consequences (ARF, arrhythmias).
DEFINITION :

4. CLASSIFICATION
1. Hande-Garrow :The 1993 classification system distinguished
between laboratory versus clinicalTLS in the four days following
treatment, but did not take into account patients who already had
abnormal laboratory values prior to treatment or those who
developed metabolic abnormalities at a later time.
2. Cairo-Bishop : proposed in 2004, modified the Hande-Garrow
classification by providing specific laboratory criteria for the
diagnosis of TLS both at presentation and within seven days of
treatment . It also a grading system .

5.  LaboratoryTLS was defined as any two or more serum
values revealing the following abnormalities :
 Serum uric acid ≥8 mg/dL (476 micromol/L) or 25 percent increase
from baseline
 Serum potassium ≥6.0 mmol/L or 25 percent increase from baseline
 Serum phosphate ≥6.5 mg/dL (2.1 mmol/L) in children, ≥4.5 mg/dL
(1.45 mmol/L) in adults, or a 25 percent increase from baseline in
either age group
 Serum calcium ≤7 mg/dL (1.75 mmol/L) or 25 percent decrease from
baseline
 These abnormalities must be present within three days before or
seven days after chemotherapy in the setting of adequate hydration
(with or without alkalinization) and use of a hypouricemic agent.

7.  ClinicalTLS (CTLS), was defined as laboratoryTLS plus
one or more of the following that was not directly or
probably attributable to a therapeutic agent:
 increased serum creatinine concentration (≥1.5 times the upper limit
of normal)
 cardiac arrhythmia/sudden death
 seizure.

8.  A grading system for severity ofTLS (on a scale from zero
to five) was based upon:
• The degree of elevation in serum creatinine.
• The presence and type of cardiac arrhythmia.
• The presence and severity of seizures .

10. Risk of tumor lysis by tumor type
• Highest risk : Burkit lymphoma, B- ALL.
• Lower risk: pre B-ALL,T- ALL, AML, high grade NHL,
CLL, MM.
• Rare (solid tumors) : SCLC, germ cell tumors, breast
cancer, neuroblastoma , medulloblastoma , ovarian
cancer and sarcomas.

11. Risk factors
 High tumor cell proliferation rate:
highest risk: Burkit lymphoma, lymphoblastic lymphoma.
 chemosensitivity .
 Tumor burden: Bulk,WBC > 50,000, LDH > 2 times ULN.
 pre treatment hyperuricemia (serum uric acid >7.5 mg/dL [446
micromol/L]) or hyper phosphatemia.
 Pre existing renal impairment.
 Oliguria / acidic urine.
 Volume depletion.

12. Risk stratification in AML
o four pretreatment laboratory findings were independent risk factors
forTLS:
1. serum LDH above laboratory normal values,
2. serum creatinine ≥1.4 mg/dL (124 micromol/L),
3. pretreatment serum uric acid >7.5 mg/dL (446 micromol/L),
4. and white blood cell (WBC) count ≥25,000/microL .

13. PATHOGENESIS

14.  Hyperuricemia :
 Hyperuricemia is a consequence of the catabolism of purine nucleic
acids to hypoxanthine and xanthine and then to uric acid via the
enzyme xanthine oxidase .
 Uric acid is poorly soluble in water, particularly in the usually acidic
environment in the distal tubules and collecting system of the
kidney.
 Overproduction and over excretion of uric acid inTLS can lead to
crystal precipitation and deposition in the renal tubules, and acute
uric acid nephropathy with acute renal failure.
 With the development of effective hypouricemic agents
(rasburicase and allopurinol), hyperphosphatemia has become the
major metabolic complication associated withTLS .

16.  Hyperphosphatemia :
 The phosphorus concentration in malignant cells is up to four times
higher than in normal cells.
 Thus, rapid tumor breakdown often leads to hyperphosphatemia
which can cause secondary hypocalcemia.
 When the calcium concentration times phosphate concentration
(the calcium phosphate product) exceeds 60 mg2/dL2, there is an
increased risk of calcium phosphate precipitation in the renal
tubules, which can lead to renal failure. In addition, precipitation in
the heart may lead to cardiac arrhythmias.

17.  Xanthinuria :
 Allopurinol blocks the catabolism of hypoxanthine and xanthine,
leading to an increase in the levels of these metabolites .
 Xanthine is much less soluble than uric acid.
 Differences in xanthine and uric acid solubility and a urine pH of 5.0
and 7.0 :
 Total uric acid solubility in urine increases from approximately 15
mg/dL at a urine pH of 5.0 to 200 mg/dL (11896 micromol/L) at a
urine pH of 7.0.
 Xanthine solubility in urine increases from approximately 5 mg/dL at
a urine pH of 5.0 to 13 mg/dL at a urine pH 7.0.

18.  patients with massiveTLS who are receiving allopurinol are at risk
for xanthine precipitation in the tubules, resulting in acute renal
failure and xanthine stone formation, despite adequate hydration
and urinary alkalinization .

20. CLINICAL MANIFESTATIONS
o The symptoms associated withTLS largely reflect the associated
metabolic abnormalities (hyperkalemia, hyperphosphatemia, and
hypocalcemia).
o They include nausea, vomiting, diarrhea, anorexia, lethargy,
hematuria, heart failure, cardiac arrhythmias, seizures, muscle
cramps, tetany, syncope, and possible sudden death .

21. PREVENTION
 Aggressive intravenous (IV) hydration is the cornerstone of
prevention ofTLS and is recommended prior to therapy in all
patients at intermediate or high risk forTLS .
 The goal of IV hydration is induction of a high urine output, which
will minimize the likelihood of uric acid precipitation in the tubules.

22.  The 2008 International Expert Panel recommended that both
children and adults initially receive 2 to 3 L/m2 per day of IV fluid (or
200 mL/kg per day in children weighing ≤10 kg) . Urine output should
be monitored closely and maintained within a range of 80 to 100
mL/m2 per hour (4 to 6 mL/kg per hour if ≤10 kg).
 Diuretics can be used to maintain the urine output, if necessary, but
should not be required in patients with relatively normal renal and
cardiac function.

23. Urinary alkalinization
o The role of urinary alkalinization with either acetazolamide and/or
sodium bicarbonate is unclear and controversial .
o In the past, alkalinization to a urine pH of 6.5 to 7.0 or even higher
was recommended to convert uric acid to the more soluble urate
salt, thereby diminishing the likelihood of uric acid precipitation in
the tubules.

24.  However, this approach has fallen out of favor for the following
reasons:
1. There are no data demonstrating the efficacy of this approach.
2. Alkalinization of the urine has the potential disadvantage of
promoting calcium phosphate deposition in the kidney, heart, and
other organs in patients who develop marked hyperphosphatemia
once tumor breakdown begins.

25.  Based upon these observations, the expert panel
concluded :
1. use of sodium bicarbonate was only indicated in patients with
metabolic acidosis .
2. The panel could not reach a consensus regarding alkalinization in
patients who will receive treatment with allopurinol but suggested
that high serum phosphate levels may preclude the use of sodium
bicarbonate in such patients .
3. Alkalinization of the urine is not required in patients receiving
rasburicase.

26. Hypourecemic agents:
A. Allopurinol. (xanthine oxidase inh).
B. Rasburicase (recombinant urate oxidase).

27. RASBURICASE ALLOPURINOL
• Recombinant urate oxidase.
• Reduction of UA in 4 hours.
• Dose: 0.15-0.2mg/kg daily 3-7
days.
• No need for alkalinization.
• Xanth oxidase inh.
• Late reduction after 48 h.
• 100mg/²m q 8 h(maximum
800mg/d).
• Alkalinization, controversial.

28. Rasburicase ALLOPURINOL
• Precautions:CI in G6PD,
methemoglobinemia, watch for
anaphylaxis.
• Timing: start 4 hours before
chemotherapy.
• SE: hemolysis in G6PD def,
methemoglobenemia,
anaphylaxis.
• Cost : 4400 $ for a 70 kg adult.
• Precautions: allergy to
allopurinol (CI), interactions (6-
MP, azathioprine, MTX,
cytarabine).
• Start 24- 48 hr before
chemotherapy.
• SE: allergy, xanthinuria,
interactions.

29. Using urate oxidase in high risk patients
reduced the need for dialysis
Needed
dialysis
DiseaseDrugNo.Author
3.5 %ALL, st 3,4 NHLrecomb urate
oxidase
57Patte C; et al
21 %ALL, Burkit
lymph
Allopurinol133Bowman WP;
et al
0 %Aggressive NHLRasburicase100Coiffier B; et al
Children 1.5%
Adults 5 %
High risk lymph
and leukemia
Rasburicase682 children
387 adults
Jeha S;
Rasb 0% ,
allopurinol 4 %
High risk
leukemias/lymp
homas
Rasburicase
versus
allopurinol
52 randomisedGoldman SC; et
al

30.  RESUTS OF A RANDOMISED COMPARATIVE PHASE 3
TRIAL OF RASBURICASEVERSUS ALLOPURINOL ON
SERUM URIC ACID CONTROL IN ADULT PATIENTS WITH
HEMATOLOGIC MALIGNANCIES AT RISK OF
DEVELOPINGTUMOR LYSIS SYNDROME:
Blood 2008; 112: abstract 919.

31.  A prospective, randomized, controlled phase III study was conducted
in adult pts to compare the efficacy of RAS (0.20 mg/kg/d, IV) days 1-
5, versus RAS+ALLO (RAS 0.20 mg/kg/d, IV days 1-3 plus oralALLO
300 mg/day days 3-5) versus ALLO alone (300 mg/d) days 1-5.
 280 pts (275 evaluable) with hematological malignancies at high or
potential risk forTLS were enrolled.
 92 pts received RAS, 92 pts received RAS+ALLO, and 91 received
ALLO.

32. PHASE 3 TRIAL: RASBURICASE VS ALLOPURINOL
AllopurinolRasburicase +
Allopurinol
Rasburicase
66 %78 %87 %Normalization of
UA at 3-7 days
72 hours4.1 hoursTime to control
of UA
No endpoints of incidence of RF or survival
were reported

33.  There were no significant differences in the incidence or severity of
adverse events, serious adverse events or deaths.The majority of
RAS and/orALLO-related adverse events were grade 1 and 2, and
most of these events were hypersensitivity-related reactions. No
cases of anaphylaxis, methemoglobinemia or hemolysis were
observed with RAS treatment.

34. TREATMENT OF ESTABLISHED TLS
 Despite appropriate preventive measures, approximately
3 to 5 percent of patients treated with rasburicase still
develop laboratory and/or clinical evidence ofTLS.

35. Electrolyte abnormalities
 General guidelines for management of electrolyte abnormalities
associated withTLS were provided by the 2008 International Expert
Panel.These guidelines are valid for children, but some modification
is needed in adults
 To avoid calcium-phosphate precipitation, most patients with acute
hypocalcemia and hyperphosphatemia due toTLS should not be
treated with calcium until hyperphosphatemia is corrected .
 Patients with severe symptoms of hypocalcemia (eg, tetany or
cardiac arrhythmia) should be considered for calcium replacement
regardless of the phosphate level.

36.  Despite hypouricemic treatment, hyperphosphatemia remains a
major problem inTLS and can cause acute kidney injury. Strategies
aimed at lowering serum phosphate levels (aggressive hydration and
phosphate binder therapy) should be used in conjunction with
control of uric acid in patients who have establishedTLS or who are
at high risk of developingTLS.

37. Management of electrolyte abnormalities
in tumor lysis syndrome

39. Indications for dialysis
 Despite the efficacy of rasburicase , approximately 1.5 percent of
children and 5 percent of adults require dialysis during induction
therapy .
 A renal consultation should be obtained immediately if the urine
output is low, hyperuricemia persists, or there is persistent
hyperphosphatemia and/or hypocalcemia .
 The prognosis for complete recovery of renal function is excellent if
dialysis is initiated early to rapidly reduce serum uric acid and
phosphate concentrations.

40. Risk stratification and recommendation -
international expert panel guidelines (2008)

41. High-risk :
 Included in the high-risk group (>5 percent risk ofTLS) are :
 All Burkitt leukemia, stage III or IV Burkitt lymphoma or early stage
Burkitt lymphoma with serum LDH level two or more times the
upper limit of normal (≥2xULN)
 Other ALL with aWBC ≥100,000 per microL and/or serum LDH level
≥2X ULN
 AML withWBC ≥100,000 per microL
 Stage III or IV lymphoblastic lymphoma or early stage lymphoblastic
lymphoma with serum LDH level two or more times the upper limit
of normal (≥2X ULN)

42.  Any adultT-cell lymphoma, peripheralT-cell, transformed and
mantle cell lymphoma with bulky tumor mass and serum LDH level
above the ULN
 Stage III or IV childhood diffuse large B-cell lymphoma with serum
LDH level ≥2X ULN
 Patients with intermediate risk disease (see below) with renal
dysfunction and/or renal involvement, or uric acid, potassium, or
phosphate levels above the ULN
 Recommendations of the expert panel : they recommend
that all high-risk patients receive aggressive intravenous hydration
and prophylactic rasburicase rather than allopurinol prior to
treatment initiation (unless they have G6PD deficiency) .

43.  Intermediate-risk :
 The intermediate-risk group (risk ofTLS 1 to 5 percent) included :
 Adult intermediate grade NHL (adultT-cell, diffuse large B-cell,
peripheralT-cell, transformed, or mantle cell lymphoma), non-bulky,
with serum LDH level above ULN
 Stage III or IV childhood anaplastic large cell lymphoma with serum
LDH level <2X ULN
 Stage III or IV childhood diffuse large B-cell lymphoma with serum
LDH level ≥2X ULN
 Early stage Burkitt lymphoma with serum LDH level <2X ULN
 ALL withWBC <100,000/microL and serum LDH level <2X ULN

44.  AML withWBC 25,000 to 100,000/microL, or AML with
WBC<25,000/microL and LDH ≥ 2X ULN
 Early stage lymphoblastic lymphoma with serum LDH level <2X ULN
 CLL treated with fludarabine or rituximab and/or those with a high
WBC (≥50,000/microL)
 Rare bulky solid tumors that are sensitive to chemotherapy (such as
neuroblastoma, germ cell cancer, small cell lung cancer)
 Recommendations of the expert panel : they generally use
allopurinol rather than rasburicase for prophylaxis in most of these
patients in the absence of pretreatment hyperuricemia. An
alternative approach is administration of a single dose of rasburicase
.

45.  Low-risk :
 Patients at low risk forTLS (<1 percent risk) include :
 AML withWBC <25,000/microL and serum LDH level <2X ULN
 CLL with aWBC ≤50,000/microL and not treated with
fludarabine/rituximab
 Multiple myeloma and CML
 Adult intermediate-grade NHL and serum LDH level within normal
limits
 Other solid tumors

46.  Recommendations of the expert panel : hydration but do
not administer any form of prophylactic hypouricemic therapy or
phosphate binders to patients in the low-risk category.This is in
agreement with the expert panel recommendation for a "watch and
wait" approach with close monitoring rather than routine
prophylaxis in these patients .

47. Hypercalcemia of malignancy

48.  Hypercalcemia is relatively common in patients with cancer,
occurring in approximately 20 to 30 percent of cases .
 Cancer is the most common cause of hypercalcemia in hospitalized
patients.
 The most common cancers associated with hypercalcemia are
breast and lung cancer and multiple myeloma .
 Patients often have poor prognosis.

49. pathogenesis
 Bone resorption and release of calcium from bone :
• Release of PTHrP. (eg Squamous cell lung cancer) :The most
common ( 80 % ).
• Osteolytic metastasis and local release of cytokines ( 20 % ).
• Tumor production of 1,25-dihydroxyvitamine D.
• Ectopic secretion of PTH .

51. Signs and Symptoms
 General: dehydration, weakness, fatigue & pruritus.
 CNS :hyporeflexia, proximal myopathy ,mental status changes,
seizure &coma.
 GI/GU: nausea/vomiting,constipation,polyuria, polydipsia,
azotemia& pancreatitis.
 cardiac : bradycardia, short-QT interval, wideT wave, prolonged PR
interval, arrhythmias & arrest.

52. Treatment of hypercalcemia
 Hydration with NS. Start at rate 200-300 ml/hr , adjust to keep
urine output 100-150 ml/h. Monitor for overload +/- loop
diuretics.
 Bisphosphonates: they inhibit Calcium release by interfering
with osteoclast activity.
• Potent, but slow action, maximum effect after 2-4 days.
• Currently available agents: pamidronate and zoledronate.
• Zoledronate: more rapid administration but higher
osteonecrosis of jaw.

53. Zoledronic Acid Is Superior to Pamidronate in the
Treatment of Hypercalcemia of Malignancy…???

54.  PURPOSE:
 Two identical, concurrent, parallel, multicenter, randomized, double-
blind, trials were conducted to compare the efficacy and safety of
zoledronic acid and pamidronate for treating hypercalcemia of
malignancy (HCM).
 PATIENTS AND METHODS:
 Two hundred eighty-seven patients were randomized with
moderate to severe HCM (corrected serum calcium [CSC] > or = 3.00
mmol/L [12.0 mg/dL]) were treated with a single dose of zoledronic
acid (4 or 8 mg) via 5-minute infusion or pamidronate (90 mg) via 2-
hour infusion.
 Clinical end points included rate of complete response by day 10,
response duration, and time to relapse.

55. •Although renal toxicity was higher with zoledronate.
CONCLUSION:
Zoledronic acid is superior to pamidronate;
4 mg is the dose recommended for initial treatment of HCM and 8 mg for relapsed
or refractory hypercalcemia .

56.  Calcitonin: decrease bone reabsorption by interference with
osteoclast maturation.
• Less effective than bisphosphonates but more rapid onset of
action. (decrease ca by 1-2 mg/ dl within 4-6 hours).
 Glucocorticoids:
• Most useful 2ry to vit D “intoxication, granulomas or 1,25
dihydroxyvitamin D producing malignancies (eg.
Lymphomas).
• Prednisolone 20-40 mg/day.
• Calcium level decrease in 2-5 days.

57.  Gallium nitrate:
• effective as bisphosphonates (pamidronate).
Cvitkovic F; Cancer J. 2006 Jan-Feb;12(1):47-53.
• It is effective for both PTHrP and non PTHrP hyprcalcemia (in
contrary with bisphosphonates ).
• Its use is limited by nephrotoxicity, the need to be infused over
5 days and limited availability.
 Dialysis:
• In severe hypercalcemia and renal insufficiency.

58.  Mild hypercalcemia :
Asymptomatic /mildly symptomatic(ca <12mg/dL)
 Do not require immediate treatment.
 Adequate hydration.
 Avoid factors that can aggravate hypercalcemia.
 Moderate- sever hypercalcemia:
 Symptomatic, ca 12 - 14 mg/dL.
 Ca >14 mg/dL.

59. 1.Volume expansion :
Isotonic saline 1 - 2 L /1 hr followed by 300-400 mL /hr ,Small doses
of furosemide may be used when the patient's volume status has
first been restored.
2. Calcitonin:(4 IU/kg ) s.c. or i.m. every 12 hrs.
3. Bisphosphonate :
Concurrently administered with Calcitonin.
 Zoledronic acid (4 mg IV over 15 min).
 Pamidronate (60 -90 mg over 2 hrs).

60. Superior vena cava syndrome

61. introduction
 Superior vena cava (SVC) syndrome results from any condition
that leads to obstruction of blood flow through the SVC.
Obstruction can be caused by invasion or external
compression of the SVC by adjacent pathologic processes
involving the right lung, lymph nodes, and other mediastinal
structures, or by thrombosis of blood within the SVC, or both.

62. ETIOLOGY
A. malignant : became the most common cause, accounting for 90
percent of cases by the 1980.
 An intrathoracic malignancy is responsible for 60 to 85 percent of
cases of SVC syndrome .
 Non-small cell lung cancer (NSCLC) is the most common malignant
cause of SVC syndrome, accounting for 50 percent of all cases .
 small cell lung cancer (SCLC, 25 percent of all cases) .
 non-Hodgkin lymphoma (NHL, 10 percent of cases).
(Together, lung cancer and NHL are responsible for approximately 95 percent of
cases of SVC syndrome that are caused by malignancy )…
 Other — Other malignant tumors that are less commonly
associated with the SVC syndrome include thymoma , primary
mediastinal germ cell neoplasms , mesothelioma, and solid tumors
with mediastinal lymph node metastases (eg, breast cancer)

63. B. non malignant:
 infection (tuberculosis , syphilitic thoracic aortic
aneurysms ),
 fibrosing mediastinitis ( primary/2nd to infections like
histoplasmosis, tuberculosis )
 Postradiation local vascular fibrosis.
 thrombosis largely because of increased use of
intravascular devices such as catheters and pacemakers.

64. Clinical manifestations
 Symptoms:
• Dyspnea: most common.
• Fascial swelling, head fullness, arm swelling.
• Cough, chest pain, dysphagia.
• Positional worsening of symptoms.
 Signs:
• Facial swelling/ edema, swelling of neck and arms.
• Facial cyanosis > plethora.
• Dilated collateral veins.
 Most cases develop gradually over weeks.

66. Imaging studies
 CXR:
• Abnormal in most cases.
• Mediastinal widening, lung masses, effusions.
 CT scan with contrast:
• The most useful study. High specificity and sensitivity (96 & 92 %).
• Assessment of tumor extent.
 Venography:
• Bilateral upper extremity venography is the gold standard for
identification of SVC obstruction and the extent of associated
thrombus formation .

67.  MR venography —
• Magnetic resonance venography is an alternative approach that may
be useful for patients with contrast dye allergy or those for whom
venous access cannot be obtained for contrast enhanced studies .

68. TREATMENT

69. General principles
 The goals of management for SVC syndrome associated with
malignancy are :
• to alleviate symptoms and treat the underlying disease.
• Treatment of the underlying cause depends upon the type of cancer,
the extent of disease, and the overall prognosis, which is closely
linked to histology and whether or not prior therapy has been
administered .These factors all influence the choice of treatment.
 The average life expectancy among patients who present with
malignancy-associated SVC syndrome is approximately six months,
but there is wide variability depending on the underlying malignancy
 Evidence-based guidelines for management of SVC syndrome are
not available .

70.  Current management guidelines stress the importance of accurate
histologic diagnosis prior to starting therapy
 Initial management should be guided by the severity of symptoms
and the underlying malignant condition as well as the anticipated
response to treatment.

72. Need for emergent RT…..???!!

73.  In the past, SVC syndrome due to malignant disease was considered
a potentially life-threatening medical emergency requiring
immediate RT as the quickest way to relieve the obstruction.
 Emergency RT is no longer considered necessary for most patients
for several reasons:
1) Symptomatic obstruction is often a prolonged process developing
over a period of weeks or longer prior to clinical presentation.The
duration of symptoms has no influence on treatment outcomes
2) RT prior to biopsy may obscure the histologic diagnosis

74.  Current management guidelines stress the importance of accurate
histologic diagnosis prior to starting therapy , and the upfront use of
endovascular stents in severely symptomatic patients to provide
more rapid relief than can be achieved using RT.
 Important exceptions to this general approach are patients who
present with stridor due to central airway obstruction or severe
laryngeal edema, and those with coma from cerebral edema.These
situations represent a true medical emergency, and these patients
require immediate treatment (stent placement and RT) to decrease
the risk of sudden respiratory failure and death

75. Supportive care and medical management
 Although there are no data documenting the effectiveness of this
maneuver, the head should be raised to decrease hydrostatic
pressure and head and neck
 the use of intramuscular injections in the arms should be avoided
(delayed absorption of drugs from the surrounding tissues )
 For patients who have obstruction of the SVC resulting from
intravascular thrombus associated with an indwelling catheter,
removal of the catheter is indicated, in conjunction with systemic
anticoagulation

76. A. Glucocorticoids : There are two settings in which systemic
administration of glucocorticoids may be helpful
o SVC syndrome caused by steroid-responsive malignancies such as
lymphoma or thymoma
o In patients undergoing RT, particularly if laryngeal edema is
present, glucocorticoids are commonly prescribed to reduce
swelling.
B . Diuretics : Diuretics are also commonly recommended,
although it is unclear whether venous pressures distal to the
obstruction are affected by small changes in right atrial pressure

77. Chemotherapy
 small cell lung cancer, NHL, and germ cell tumors :
 For patients with SCLC , NHL, or germ cell cancer (and possibly
breast cancer), initial chemotherapy is the treatment of choice for
patients with symptomatic SVC syndrome. In these settings, the
clinical response to chemotherapy alone is usually rapid
 Symptomatic improvement usually occurs within one to two weeks
of treatment initiation
 For these malignancies, use of RT alone usually yields poorer long-
term results and may compromise the subsequent results of
chemotherapy

78.  Non-small cell lung cancer :
 The degree and rapidity of response to chemotherapy is less in
NSCLC. Symptom relief in this setting is more rapidly achieved by
the use of an endovascular stent.
 SVC obstruction is a strong predictor of poor prognosis in patients
with NSCLC, with a median survival of only five months in one series.

79. Radiation therapy
 Radiation therapy (RT) is widely used for SVC syndrome caused by
radiosensitive tumors in patients who have not been previously
irradiated.When effective, RT provides considerable relief by
reducing tumor burden .
 Most of the malignancies causing SVC syndrome are radiation-
sensitive, and at least in lung cancer, symptomatic improvement is
usually apparent within 72 hours .

80. Endovascular stents
 The placement of a self-expanding endovascular stent restores
venous return and provides rapid and sustained symptom palliation
in patients with SVC syndrome.The technical success rate is in the
range of 95 to 100 percent, and over 90 percent of patients report
relief of symptoms.
 The stent is placed percutaneously via the internal jugular,
subclavian, or femoral vein, under local anesthetic .
 No significant difference in the published outcomes of the three
most commonly used stainless steel stents (Gianturco Z stent, the
Palmaz stent, or theWallstent)
 There are no randomized trials comparing the efficacy of
endovascular stents with palliative RT or systemic chemotherapy.

81.  Indications for stenting :
1. severe symptoms who require urgent intervention.
2. for rapid symptom palliation in patients with NSCLC and
mesothelioma .
3. for those with recurrent disease who have previously received
systemic therapy or RT.
 Thrombolytic therapy :
 local catheter-directed thrombolytic therapy may be of value to
reduce the length of the obstruction and the number and length of
stents required, and also reduce the risk of embolization .
 Thrombolytic therapy has also been administered following
placement of an endovascular stent in an attempt to decrease
secondary reocclusion .
 However, the benefit of thrombolytics in this setting remains
unclear.

82. Surgical intervention
 Although effective and associated with relatively few complications ,
surgical bypass is rarely performed in patients with malignant cause
of SVC syndrome because of the success of endovascular stenting.
Surgical management is more often undertaken in patients with
benign causes of SVC syndrome.

83. Treatment recommendations:
 Non emergent cases ( majority) (no laryngeal edema,
strider or brain edema/coma):
• Obtaining a tissue diagnosis is a priority.
• Avoid interventions that may affect interpretation of the biopsy
(steroids and radiotherapy).
• Tumors that are responsive to chemotherapy: SCLC, NHL, germ cell
tumors: primary chemotherapy – improvement in symptoms in 1-2
weeks.
• Tumors that are less responsive to chemotherapy: NSCLC,
thymoma.Initiate RT or chemo-RT.
• In severely symptomatic patients, consider intravascular stents as
initial therapy.

84.  Emergent cases (laryngeal edema, strider, coma):
• Endovascular stents are the most effective.
• Initiate without delay.
 Supportive measures:
• Elevation of the head of bed.
• Oxygen
• Diuretics.
• Steroids: if laryngeal, brain edema, with RT.And after obtaining
biopsy.

85. Treatment algorithm of superior vena cava
syndrome

86. Yu, JB, Wilson, LD, Detterbeck, FC. Superior vena cava syndrome-a proposed classification system and algorithm for
management. J Thorac Oncol 2008; 3:811.

87. EPIDURAL SPINAL CORD
COMPRESSION

88. EPIDEMIOLOGY and Causes :
 Neoplastic epidural spinal cord compression (ESCC) is a common
complication of cancer that can cause pain and potentially irreversible
loss of neurologic function .
 Most cord compression cases involve tumor or collapsed bone
fragments in the epidural space, a few cases are subdural, and
intramedullary metastases are very rare.
 Many cancer patients have asymptomatic or unrecognized ESCC,
while others develop ESCC .

90.  The three most common are prostate cancer, breast cancer, and
lung cancer, each of which accounts for about 20 percent of cases ,
Renal cell carcinoma, non-Hodgkin lymphoma, and plasmacytoma
or multiple myeloma are other frequent causes of ESCC .

91.  The tumors responsible for ESCC in children are different. Sarcomas
(especially Ewing) and neuroblastomas are the most frequent
causes, followed by germ cell neoplasms and Hodgkin lymphoma.
 Approximately 20 percent of cases of ESCC are the initial
manifestation of malignancy.
 The thoracic spine is most often involved (60%-70%), followed by
the lumbosacral (20% - 30%) and cervical spine (10%) .

92. DIAGNOSIS

93. Clinical features
 Early recognition of the clinical features of ESCC offers more hope of
improving outcome than any advances in diagnosis or treatment,
the goal must be to establish the diagnosis prior to the development
of spinal cord damage .
 Unfortunately, the diagnosis is often delayed in patients who have
symptoms of back pain for as much two or three months before the
diagnosis is established.

94.  Pain: Pain is usually the first symptom , being present in 83 to 95
percent of patients at the time of diagnosis ,On average, pain
precedes other neurologic symptoms of ESCC by seven weeks
affected patients usually notice a severe local back pain which
progressively increases in intensity
 Motor findings :Weakness is present in 60 to 85 percent of patients
with ESCC at the time of diagnosis
 Sensory findings :Sensory findings are less common than motor
findings but are still present in a majority of patients at diagnosis .
Patients frequently report ascending numbness and paresthesias if
questioned and examined carefully.
 Bladder and bowel dysfunction :is generally a late finding that may be
present in as many as one-half of patients
 Ataxia :

95. Radiologic confirmation
 Magnetic resonance imaging :
Potential advantages of MRI compared to other imaging modalities
include:
 MRI produces anatomically of the spinal cord and intramedullary
pathology. MRI also defines the adjacent bone and soft tissues.
 MRI can image the entire thecal sac regardless of whether a spinal
subarachnoid block is present.
 MRI is not contraindicated in patients with brain metastases,
thrombocytopenia, or coagulopathy.
 MRI avoids the need for a lumbar or cervical puncture, which is
required with myelography.

96.  Myelography:
CT myelogram with MRI found that the two technologies were
roughly equivalent in sensitivity and specificity . CT myelography is
still widely used in treatment planning for radiosurgery .

97.  Other modalities :
 None are reliable enough to replace either MRI or myelography as an
initial screening procedure.
1. Computed tomography — CT of the spine does not
demonstrate the spinal cord or epidural space clearly
2. Radiography
3. Bone scan not informative about thecal sac
compression

98. PRIMARYTREATMENT

99.  The goals of treatment for patients with ESCC include :
• pain control,
• avoidance of complications,
• and the preservation or improvement of neurologic function utilizing
 Impact of treatment delay on posttreatment
ambulation:
• The single most important prognostic factor for regaining
ambulation after treatment of an ESCC is pretreatment neurologic
status .

100. General principles of treatment
 Management of patients with ESCC includes the immediate
administration of glucocorticoids in all patients, followed by surgery,
external beam radiation therapy (EBRT), or stereotactic body
radiotherapy (SBRT). Systemic therapy may be beneficial in patients
with chemosensitive tumors
 Symptomatic treatment of ESCC often begins prior to definitive
therapy and consists of the following general principles :
1. Pain management
2. Bed rest :There is generally no need to confine the patient to bed.
3. Anticoagulation : anticoagulation should be considered if the
patient is immobilized due to the ESCC .
4. Prevention of constipation

101. Glucocorticoids
 Only three clinical trials have addressed the utility and optimal initial
dose of glucocorticoids in ESCC.
 In one study, 57 patients with carcinoma (two-thirds with a primary in the breast) and
myelographically confirmed ESCC were randomly assigned to receive either
dexamethasone(96 mg intravenously followed by 24 mg four times daily for three
days and then tapered over 10 days) or no dexamethasone .
 all patients received standardized RT.
 Effect of high-dose dexamethasone in carcinomatous metastatic spinal
cord compression treated with radiotherapy: a randomised trial.
Sorensen S; Helweg-Larsen S; Mouridsen H; Hansen HH

102.  Conclusion :
• A significantly higher percentage of patients in the dexamethasone
group remained ambulatory both at the end of therapy (81 versus 63
percent) and at six months (59 versus 33 percent).
• Significant side effects were seen in three patients (11 percent in the
steroid group).
XRTDexa + XRT
63 %81 %Ambulatory (end of
treatment)
33 %59 %Ambulatory(6m)

103. High versus low dose of dexamethasone
 A pilot randomised comparison of dexamethasone 96 mg vs 16 mg per
day for malignant spinal-cord compression treated by radiotherapy:TROG
01.05 Superdex study. Graham PH;et al, Clin Oncol (R Coll Radiol). 2006
Feb;18(1):70-6.
•The optimal initial dose of steroids was addressed in a small trial in which 20 patients
undergoing RT (30 Gy in 10 fractions) were randomly assigned to 96 or 16 mg of
dexamethasone daily for the first 48 hours, followed by a rapid taper over 15 days .
 Conclusion :
•The incidence of serious adverse events was five of nine in the high-dose and four of
11 in the low-dose group.
•There were no advantages for pain control or one month ambulation with high dose
steroids

104.  Initial bolus of conventional versus high-dose dexamethasone in
metastatic spinal cord compression.Vecht CJ;et al; Neurology 1989
Sep;39(9):1255-7.
In another trial that attempted to identify the optimal corticosteroid dose, 37
patients with ESCC were randomly assigned to an initial dexamethasone bolus of
10 mg or 100 mg intravenously, both followed by 16 mg daily orally. There were
no differences in pain control or neurologic outcome between the two groups
Conclusion No difference in pain or neurologic function.

105. High incidence of serious side effects of high-dose
dexamethasone treatment in patients with epidural spinal cord
compression
Heimdal K; Hirschberg H; Slettebo H; Watne K; Nome
J Neurooncol 1992 Feb;12(2):141-4
• 28 received high dose 96 mg loading, tapering over
2 weeks.
•38 received 16 mg daily, tapered over 2 weeks.
•All patients received RT.
Adverse events
Serious eventsAll events
14 % *28 %High dose
0 %8 %Low dose
Higher initial doses were not
associated with better
outcomes, but they were
associated with a higher
incidence of serious adverse
events (such as perforated
gastric ulcer, psychosis, and
death from infection).

106. Definitive treatment

107. Role of surgery
• Laminectomy
• A retrospective analysis of case series of patients treated with
laminectomy with or without RT versus RT alone showed no benefit
of laminectomy.
(Findlay GF, J Neurol Neurosurg Psychiatry 1984 Aug;47(8):761-8.)
• A small randomised trial (laminectomy + RT vs. RT alone) found no
difference in pain relief, ambulation or sphincter function.
(Young RF; Post EM; KingGA, J Neurosurg 1980 Dec;53(6):741-8.)

108. Radical resection plus radiotherapy
• improvement in surgical techniques had lead to increasing use of
tumor debulking surgery followed by surgical reconstruction to
manage spinal cord compression.
• Anterior stabilization using either bone grafting or
methylmethacrylate.
• Methylmethacrylate is preferable because it allows earlier initiation
of RT ( 1 wk post op vs. 6 wk).

109.  Direct decompressive surgical resection in the
treatment of spinal cord compression caused by
metastatic cancer: a randomised trial.
(Patchell RA;Tibbs PA; RegineWF)
(Lancet. 2005 Aug 20-26;366(9486):643-8.)
• 101 patients with spinal cord compression randomised to surgery +
RT (n=50) or RT alone (n=51).
• RT = 30 Gy / 10 Fr to all patients.
• After 1st interim analysis, the study was closed because significantly
more patients in the surgery arm were able to walk by the end of
treatment ( 84 % vs. 57 % ).

110. • Patinets in surgery arm retained the ability to walk significantly
longer ( 122 days vs. 13 days, p=0.003).
• The need for steroids and opioids was significantly reduced in the
surgery group.
 Conclusion:
 Direct decompressive surgery plus postoperative radiotherapy is
superior to treatment with radiotherapy alone for patients with
spinal cord compression caused by metastatic cancer.

111. prognosis
• Median survival : 6 months.
• Better for patients ambulatory prior to RT( 8-10 months vs 2-4 m ).
• Those who remain non ambulatory after RT, MS 1 month.
• Type of cancer.Worse in NSCLC (MS 3 m).
• Worse prognosis with multiple vertebral vs solitary vertebral Mets. ,
worse with visceral and brain Mets compared to isolated bone Mets.

112. Thank you…..